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Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned... Review published: 05 April 2017 doi: 10.3389/fimmu.2017.00294 interactions between Type 1 interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases 1 2 1 3 Bas C. Mourik , Erik Lubberts , Jurriaan E. M. de Steenwinkel , Tom H. M. Ottenhoff and Pieter J. M. Leenen * Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, Netherlands, 2 3 Department of Rheumatology, Erasmus University Medical Center, Rotterdam, Netherlands, Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands, Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands The classical paradigm of tuberculosis (TB) immunity, with a central protective role for Th1 responses and IFN-γ-stimulated cellular responses, has been challenged by unsatisfactory results of vaccine strategies aimed at enhancing Th1 immunity. Moreover, preclinical TB models have shown that increasing IFN-γ responses in the lungs is more damaging to the host than to the pathogen. Type 1 interferon signaling and altered Th17 Edited by: responses have also been associated with active TB, but their functional roles in TB Laurel L. Lenz, pathogenesis remain to be established. These two host responses have been studied University of Colorado Denver School of Medicine, USA in more detail in autoimmune diseases (AID) and show functional interactions that are Reviewed by: of potential interest in TB immunity. In this review, we first identify the role of type 1 Roland Lang, interferons and Th17 immunity in TB, followed by an overview of interactions between University Hospital Erlangen, Germany these responses observed in systemic AID. We discuss (i) the effects of GM-CSF- Rolf Billeskov, secreting Th17.1 cells and type 1 interferons on CCR2 monocytes; (ii) convergence of Statens Serum Institut, Denmark IL-17 and type 1 interferon signaling on stimulating B-cell activating factor production *Correspondence: and the central role of neutrophils in this process; and (iii) synergy between IL-17 and Pieter J. M. Leenen [email protected] type 1 interferons in the generation and function of tertiary lymphoid structures and the associated follicular helper T-cell responses. Evaluation of these autoimmune-related Specialty section: pathways in TB pathogenesis provides a new perspective on recent developments in This article was submitted to Microbial Immunology, TB research. a section of the journal Keywords: Mycobacterium tuberculosis, autoimmune diseases, neutrophils, inflammation, tertiary lymphoid Frontiers in Immunology structures, antibodies, B-cell-activating factor Received: 21 December 2016 Accepted: 01 March 2017 Published: 05 April 2017 1. iNTRODUCTiON Citation: Tuberculosis (TB) has been responsible for an estimated one billion deaths worldwide over the last Mourik BC, Lubberts E, de Steenwinkel JEM, Ottenhoff THM 200 years (1), which is more than any other infectious disease caused by a single pathogen. Given its and Leenen PJM (2017) Interactions global magnitude, it has been hypothesized that TB particularly contributed to the genetic selective between Type 1 Interferons pressure that predisposes for development of autoimmune diseases (AID) (2). This is supported by and the Th17 Response in polymorphism studies of the TNF gene, which show an opposite association between susceptibility Tuberculosis: Lessons Learned to TB vs. susceptibility to several AID (3). Additionally, a gender-dependent predisposition to either from Autoimmune Diseases. TB or AID exists with a male predominance among TB patients (4) opposed to increased AID Front. Immunol. 8:294. doi: 10.3389/fimmu.2017.00294 incidences in women (5). The general concept of an inverse relation between infectious diseases and Frontiers in Immunology | www.frontiersin.org 1 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB AID is best described by the hygiene hypothesis, which states that by activating dendritic cells and NK cells and by stimulating both + + diminished exposure to infectious pathogens during childhood /CD8 T-cell responses. However, B-cell responses and CD4 increases the chances of developing AID and allergies (6, 7). Also, T1-IFNs can also induce anti-inflammatory responses to control epidemiologically, the decline in burden of infectious diseases immune-mediated tissue damage during chronic infections. over the last century in industrialized countries is accompanied es Th e contradictory effects of T1-IFNs in different situations by increasing rates of AID (8). can likely be ascribed to the heterogeneity of the T1-IFNs family, Despite support for an inverse relation, similarities between downstream activation of different STAT homo/heterodimers aer b ft inding to IFNAR (38, 42) and to differential priming of TB and AID have also been identified. TB is even hypothesized to be an infection-induced AID based on the observation that cells prior to induction of T1-IFN signaling (43). diverse clinical autoimmune phenomena frequently occur in TB patients (9, 10). Furthermore, up to 32% of patients with active 2.1. T1-iFNs in Human TB TB have elevated autoantibody titers (11, 12). Rational explana- When recombinant or purified T1-IFNs became available as tions for these findings could be that either TB or AID activate therapeutic agents in the 1980s, different applications have been common immunological pathways (10), or protective immunity established based on their antiviral, immune-stimulating, and in TB increases the chance to develop AID (2). In both scenarios, suppressive effects. These include treatment of viral infections key findings in AID immunology could potentially contribute to (e.g., IFN-α treatment of hepatitis B/C infections), AID [e.g., our understanding of TB pathogenesis. IFN-β treatment for multiple sclerosis (MS)], and various malig- The current paradigm of the host response to Mtb infection nancies (44). Based on their well-described immune-stimulating is summarized in Figure  1. The indispensable role of IL-12/ effect, the use of T1-IFNs as adjuvant to antibiotic treatment for IFN-γ-mediated Th1 immunity against Mtb has long been patients with active TB has also been explored (see Table 1). All recognized (13). However, stimulating Th1 immunity in TB studies found a positive influence of adjuvant T1-IFN therapy can also result in excessive inflammation (see Box  1 ). More on clinical outcomes in active TB (45–49). Conversely, IFN-α recently, the contributions of additional immune pathways treatment without concomitant antibiotic treatment, e.g., for have been explored, especially the role of type I interferons hepatitis C, has been described to cause reactivation of latent TB (T1-IFNs), Th17 immunity (14, 15), and unconventional (50–57). While reactivation of latent TB and treatment of active T  cell immunity (16–18). Little is known about the potential TB are two distinct clinical situations, the latter finding suggests interaction between T1-IFNs and Th17 responses in TB, but an unfavorable role for T1-IFNs in TB pathogenesis. interesting observations in this regard have been reported for In 2010, an interferon-inducible transcriptional signature was multiple AID (19–21). To determine if these findings are rel- reported in circulating leukocytes of TB patients, thus linking evant for the understanding of TB pathogenesis, we first review increased T1-IFN signaling with active disease (58). This find- the separate involvements of T1-IFNs and Th17 responses ing has been validated in several independent studies (59–62). in TB pathogenesis in Sections 2 and 3, respectively. Next, A meta-analysis confirmed statistical significance but found a their known interactions in AID are discussed in Section  4. less dominant role for T1-IFN-related genes than expected (63). Finally, in Section 5, the potential relevance of these interacting This is ascribed to the involvement of signaling components pathways in TB is assessed and integrated into the current downstream of the T1-IFNs receptor in multiple overlapping understanding of TB pathogenesis. intracellular pathways. Also, association studies do not neces- sarily implicate a causally detrimental effect of T1-IFNs in TB 2. T1-iFNs iN TB pathogenesis. In line with this, T1-IFN responses show potential as biomarkers or diagnostic tool for risk of active disease, but Type I interferons comprise a family of 13 IFN-α subtypes, IFN-β, their functional involvement during TB progression in patients IFN-ε, IFN-κ, and IFN-ω, which have the shared ability to bind to is not yet understood (62). the IFN-α/β receptor (IFNAR) (37). Other interferons include the single type II interferon, interferon-γ, and the type III interferon 2.2. Preclinical Studies in Mice Support a family covering three IFN-λ types. Detrimental Role of T1-iFNs during All nucleated cell types are capable of both producing T1-IFNs and responding to them, while type II/III interferons are mostly Acute TB produced by leukocytes (37). The main function of T1-IFNs is A causal relationship between T1-IFN signaling and TB disease severity was first suggested in 2001 when IFN-α levels in the to “interfere” with intracellular infections. Therefore, T1-IFN expression is primarily induced through cytoplasmic pattern lungs of Mtb-infected mice were shown to be associated with Mtb strain virulence (64). Several approaches have been used recognition receptors (PRRs) and endosomal toll-like receptors (TLRs), which activate distinct interferon regulatory factors to verify this relationship between increased T1-IFN signaling and unfavorable disease outcome. Blocking the T1-IFN signaling (IRFs) that act as transcription factors enabling expression of −/− interferon-responsive genes (38). In contrast, extracellular patho- pathway through use of IFN-α/β receptor knockout (IFNAR ) improves survival, but only when applied on the background of gens trigger surface-bound TLRs that preferentially induce IL-1β and TNF-α through activation of NF-κB. mouse strains in which acute TB is lethal, such as the A129 strain −/− (65). In IFNAR mice with a relatively TB-resistant C57BL/6 e Th role of T1-IFNs in infectious diseases is complex (15, 39– 41). T1-IFNs boost the immune system upon pathogen encounter background, survival rates were similar to wild-type mice, but Frontiers in Immunology | www.frontiersin.org 2 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB FigURe 1 | The phases and cell types involved in the immune response to tuberculosis (TB) in the lungs. (1) Inhaled Mtb-containing aerosols are deposited deep into the lung, reaching the alveoli (22). Within the alveoli, Mtb are phagocytosed by alveolar macrophages (Alv. MΦ) or infect alveolar epithelial cells prior to ending up in alveolar macrophages (23). Within Alv. MΦ, the bacteria are able to inhibit phagosome–lysosome fusion and replicate until cell lysis ensues, which takes approximately 3–5 days (24). (2) After the initial contact, Mtb encounters infiltrating myeloid cells of which inflammatory dendritic cells and PMN are most readily infected (13, 25). During these early phases, invariate natural killer (iNK) cells and type 1 innate lymphoid cells (ILC1) produce IFN-γ in response to IL-12 and stimulate myeloid cells to kill phagocytosed Mtb. In addition, γδ T-cells and ILC3 produce IL-17. There is increasing appreciation for the role of tertiary lymphoid structures (TLS) and their associated germinal centers (GC) that arise under influence of IL-17 and facilitate optimal activation of myeloid cells and efficient recall responses. During this process, loosely aggregated “innate granulomas” are already formed (26). It should be noted that the roles of ILC1s and ILC3s are based on their general function, which has not yet been formally demonstrated in TB (27). (3) Onset of adaptive immunity in Mtb infection is delayed to circa 14 days in mice and up to 6 weeks in humans (13, 22). At this point, distinct T-cell subsets and B-cells migrate to the site of infection and execute their different effector functions. (4) After onset of adaptive immunity, 90–97% of infected individuals develop sustained infection without clinical symptoms termed “latent TB infection” (LTBI) (13). LTBI was initially considered a static phase, but it is now known that this stage is hallmarked by the presence of granulomas in various stages (caseous, non- caseous, and fibrotic) and an ongoing balance between antimycobacterial activity and regulatory mechanisms to minimize immunopathology (13, 28). Cell phenotypes are as present in mouse TB models. Frontiers in Immunology | www.frontiersin.org 3 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB (67, 77–81). ESAT-6 can disrupt the phagosomal membrane, BOx 1 | The dual faces of iFN-γ in tuberculosis (TB) immunity. which allows translocation of mycobacteria and mycobacterial In the current paradigm of a successful host response, lung DCs migrate to the products from the phagosome into the cytosol (78, 82). draining lymph node after Mtb contact and induce a robust IL-12-mediated Mycobacteria actively secrete several T1-IFN-inducing com- Th1 response (13). This results in migration of IFN-γ-producing CD4 T-cells to pounds, including double-stranded (ds)DNA and the bacterial the site of infection. Subsequently, activation of macrophages by IFN-γ results in killing of intracellular Mtb, while activated CD8 T-cells lyse infected host second messenger cyclic-di-AMP (83). These compounds are cells. Conversely, unsuccessful clearance of infection is due to poor activation recognized by different cytosolic PRRs, including cGAS (80), of adaptive immunity. This can result from insufficient antigen presentation IFI-204 (78), AIM2 (84), and possibly NOD2 (77), although data (29), or from the action of regulatory factors that interfere with Th1 responses on the latter are conflicting (67, 78). Activation of these cytosolic such as IL-10 or PDL1-PD1 interaction (13). Paradoxically, the current vaccine PRRs converges to activate “STimulator of INterferon Genes” bacillus Calmette–Guérin (BCG) induces a strong Th1 response but is only partially effective in protecting against TB (30). Boosting the Th1-inducing (STING), which subsequently forms a complex with TANK- potential of BCG by using a modified Ankara virus also has yielded disap- binding kinase 1 (79). This STING–TBK1 complex activates pointing results (31, 32). Thus, solely stimulating Th1 immunity might not be IRF3, leading to IFN-β production in mice (81) as well as human the solution in TB prevention. This is confirmed in a mouse TB study showing −/− mice are poor producers of IFN-β and dendritic cells (74). IRF3 that increasing IFN-γ production by T-cells in the lungs is detrimental to the more resistant to Mtb infection, which supports a negative role host due to hyper-inflammation that requires PD-1-mediated suppression to limit pathology (33). In line with this, Mtb-infected mice deficient in PD-1, or for T1-IFNs in TB pathogenesis (78). −/− mice in which PD-1 is selectively inhibited, display excessive inflammation However, the overall picture is more complex. IRF3 mice are and disease progression (34, 35). Finally, ex vivo studies in human monocyte- more resistant to Mtb infection, but mice deficient in the cytosolic derived macrophages show that protective effects of IFN-γ are dependent on PRR cGAS, upstream of IRF3, show diminished control of chronic multiple factors including time of contact, concentration, and the magnitude of Mtb infection (79). This can be traced back to a concomitant the ensuing microbial challenge (36). Based on these observations, it can be concluded that boosting IFN-γ production and Th1 immunity in TB, besides reduction in autophagy, which is also dependent on the cGAS- potentially enhancing protection, can also result in unbalanced inflammation induced activation of the STING–TBK1 axis, but independent in the lungs that is more harmful to the host than to the pathogen. This of IRF3. In line with this, mice infected with an Mtb strain that emphasizes the need for involvement of additional immunological pathways induces higher amounts of cyclic-di-AMP, thus stimulating both for optimal protection. IRF3-mediated IFN-β production and STING–TBK1-mediated autophagy, show improved survival despite increased IFN-β levels (83). Taken together, this suggests that pro-mycobacterial mycobacterial loads in the lungs were lower (66–69). One study effects of stimulating the cytosolic PRR/STING/IRF3/IFN-β axis actually observed increased loads in the lungs (70) (Table 2). by mycobacteria might be outweighed by the antimycobacterial In a second approach, Mtb-infected mice were supplemented effects of the PRR/STING/autophagy pathway. with T1-IFNs aer ft start of infection or treated with the TLR3- Autocrine or paracrine IFN-β-signaling induces IRF7 and ligand poly-ICLC, which stimulates T1-IFN production and leads to the production of IFN-α in human dendritic cells signaling (64, 72). Both studies showed increased mortality and (74). In line with this, injection of recombinant IFN-β in mice higher mycobacterial loads in the supplemented groups, which induces IFN-α production (85). Alternatively, myeloid cells and were not observed when T1-IFNs or poly-ICLC were adminis- particularly plasmacytoid dendritic (pDC) cells are capable of −/− tered to Mtb-infected IFNAR mice. Finally, in a third approach, directly activating IRF7-mediated IFN-α production aer r ft ecog- mice were primed with a T1-IFN-inducing influenza virus prior nition of Mtb, particularly by endosomal TLR9 (86). In TB, this to TB infection, which led to enhanced mycobacterial growth and TLR9-IRF7 pathway is studied to lesser extent than the cytosolic reduced survival (73). PRR–IRF3 axis (87). This is possibly due to the dependence of −/− Enigmatically, reduced mycobacterial loads in IFNAR mice T1-IFN-mediated pathogenic effects in mice on ESX-1, which are primarily observed in the acute phase of infection in which induces IRF3 rather than IRF7 as explained above (67). However, T1-IFNs are considered immune stimulating. No differences in IRF7 is recognized as commonly induced transcription factor survival or long-term control of infection were found in C57BL/6 by multiple clinical Mtb strains in alveolar epithelial cells (88). −/− IFNAR mice compared to wild type. In support of this notion, −/− mice succumb earlier to high-dose Mtb infec- Moreover, TLR9 T-cell analyses in several of the abovementioned studies con- tion than wild-type mice, which suggests a role for the TLR9/ vincingly excluded an effect of increased or decreased T1-IFN IRF7/IFN-α axis in TB as well (89). signaling on the adaptive immune response (68, 69, 72). Notably, none of these studies addressed the effect of T1-IFNs as adjunct treatment to antibiotics, which was shown to be beneficial in TB 2.4. T1-iFNs Drive the influx of patients (Table 1). Mtb-Permissive Myeloid Cells during Acute infection 2.3. Mtb Actively induces T1-iFNs Most studies in mouse TB models found significant functional + int effects of T1-IFNs specifically on CD11b Gr1 myeloid cell Multiple studies indicate that Mtb employs both active and pas- sive mechanisms to induce T1-IFNs (74–76). The mycobacterial populations (68, 69, 72). This population comprises monocyte- high − high derived Ly6C CD11c CCR2 inflammatory macrophages ESAT-6 secretion system (ESX-1) and its 6  kDa early secre- int + int tory antigenic target (ESAT-6) are essential in this process, as (iM) and Ly6C CD11c CCR2 inflammatory dendritic cells + high (iDC), but not CD11b Gr1 PMN (90). This is an important mycobacteria lacking ESX-1 fail to induce T1-IFN production Frontiers in Immunology | www.frontiersin.org 4 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB Frontiers in Immunology | www.frontiersin.org 5 April 2017 | Volume 8 | Article 294 TABLe 1 | effect of type i interferons supplementation in human tuberculosis (TB). Study design Regimen Outcome Side effects Reference Open parallel, susceptible Mtb No adverse Giosue et al. HRZE vs. HRZE + IFN-α – Less fever on days 3 and 4 after start treatment in HRZE + IFN-α group strain, HIV (−), N = 20 (2 × 10), – Increases in total lymphocytes and HLA DR1 cells after 2 months only in HRZE + IFN-α group effects reported (45) 2 months treated – Reduction in HRCT score only in HRZE + IFN-α group – Stronger reduction of pro-inflammatory cytokines in BALF after 2 months treatment in HRZE + IFN-α group Patients treated prior for 3–12 years, Anti-TB treatment + IFN-α – 2/5 complete response Flu-like symptoms Palmero et al. MDR strain, HIV (+), N = 5, – 1/5 partial response in 4/5 patients, (46) 12 weeks treated – 2/5 no response not needing – Increase of NK (% cytotoxicity) in all patients after 12 weeks treatment Patients treated prior for 6 months, DOT + IFN-α – Significant drop (p = 0.02) in Mtb loads at the end of a 9-week IFN-α treatment course No adverse Giosue et al. MDR strain, HIV (−), N = 7, 9 weeks – Significant increase (p = 0.03) in Mtb loads after stop of IFN-α treatment effects reported (47) treated – Significant drop in IL-1β, IL-6, TNF-α, and IFN-γ pro-inflammatory cytokines; IL-4 and IL-10 showed inconsistent changes Parallel, patients treated prior for 1. DOT – After 8 weeks, all five subjects of the case group became sputum smear negative; the control group 4 subjects mild Mansoori et al. 6 months with DOT, MDR strain, HIV 2. DOT + IFN-α remained smear positive (p = 0.012) arthralgia and (48) (−), N = 12 (2 × 6), 8 weeks treated – Evaluation of smear results after 6 months showed two smear-negative subjects in the case group while all myalgia, flu-like controls were smear positive (p = 0.132) symptoms in all subjects Case report, MDR strain, HIV (−), HRZE + IFN-α – Two months after initiation of therapy, sputum smears became negative, the patient’s clinical and No adverse Zarogoulidis N = 1, 2 months treated radiological findings strikingly improved. During 4-year follow-up, all consecutive sputum cultures remained effects reported et al. (49) negative Green text indicates a host-beneficial effect in TB; BALF, bronchoalveolar lavage fluid; DOT, directly observed therapy (antibiotic TB treatment); HRCT, high-resolution computed tomography; HRZE, isoniazid, rifampicin, pyrazinamide, and ethambutol; MDR, multidrug resistant. Mourik et al. Interactions between T1-IFNs and Th17 in TB TABLe 2 | interference with T1-iFN signaling in preclinical tuberculosis (TB) studies. Mouse intervention Mtb strain Survival Mtb load Reference back ground A129 IFN-α/β receptor HN878, W4, CDC1551, Better survival against CDC1551 No data Manca et al. (65) knockout 100–200 CFU, aerosol Trend toward better survival −/− (IFNAR ) against HN878 B6D2/F1 Anti-IFN-α/β HN878, 100–200 CFU, aerosol Better survival against HN878 No differences up to day 100 Manca et al. (65) antibody −/− B6/129 IFNAR H37Rv, HN878, CSU 93, CSU No differences in survival after Lower Mtb loads in lungs after infection Ordway et al. (66) 123 50–100 CFU, aerosol infection with all strains with all strains up to day 150 −/− 6 B6 IFNAR Erdman, 10  CFU, i.v. injection No data No differences in lung until day 20 Stanley et al. (67) Lower Mtb loads in spleen at day 10 and day 20 −/− B6 IFNAR H37Rv, 100 CFU, aerosol No differences up to day 70 Lower Mtb loads in lungs at day 18, Desvignes et al. (68) no differences at day 25 −/− 129S2 IFNAR H37Rv, 200 CFU, aerosol Improved survival Lower Mtb loads at day 21 Dorhoi et al. (69) −/− B6 IFNAR H37Rv, 500 CFU, aerosol No differences in survival up to Lower Mtb loads at day 21 Dorhoi et al. (69) day 90 −/− B6.SJL IFNAR H37Rv, 100–150 CFU, aerosol No differences in survival up to No data Mayer-Barber et al. (71) day 90 −/− B6/129 IFNAR Erdman, 100 CFU, aerosol No data Higher Mtb loads in lungs on day 10, Cooper et al. (70) day 20, and day 40 Equal loads at day 80 Green text indicates a host-beneficial effect in TB, while red indicates harmful effects. i.v., intravenous; CFU, Colony Forming Units. distinction, as T1-IFNs actively inhibit PMN influx, as discussed main source of this chemokine (94–96). Expression of CCL2 is −/− in more detail in Section 2.4.3. reduced in the lungs of IFNAR mice, and the pathogenic effects −/− Inflammatory macrophages and iDC have been identified as of poly-ICLC treatment are absent in Mtb-infected CCR2 mice major contributors to disease progression in mouse TB models (72). Thus, preclinical TB studies indicate that T1-IFNs stimulate (91–93). Several lines of evidence suggest that T1-IFNs regulate the influx of CCR2 monocytes, but not PMN, to the site of the influx of these cells and play a role in their functional impair - infection in a CCR2-dependent way via the induction of CCL2 ment to resist Mtb. This interference with protective immunity in parenchymal cells (74–76). is multifaceted and concerns four important interactions, which 2.4.2. T1-IFNs Inhibit IL-1β Responses will be reviewed separately: (1) T1-IFNs mediate the influx of iM and iDC. (2) T1-IFNs inhibit IL-1β responses by these cells, which during Acute TB are essential in the initial host responses to Mtb. (3) Prolonged Type I interferons not only stimulate the influx of CCR2 mono- IL-1β signaling can also cause excessive inflammation and thus cytes but also stimulates their differentiation into Mtb-permissive requires regulation during later phases. This can be mediated by iM and iDC (72, 75, 76). This can be traced back to a cross talk T1-IFNs but also by IFN-γ through functionally different routes. between T1-IFNs and IL-1β (71, 90). iM and iDC are the major (4) T1-IFNs and IFN-γ show a complex interplay in the activation sources of IL-1β in the lungs Mtb-infected mice, and IL-1β plays of iM and iDC. a crucial role in the acute host response to Mtb infection (71, 90). IL-1β augments TNF-α-stimulated Mtb killing and increases 2.4.1. T1-IFNs Mediate the Influx of iM and iDC (PGE ) production by upregulating cyclooxyge- prostaglandin E2 2 Mtb-infected mice treated with the T1-IFN-inducing compound nase-2 (COX2/PTGS2) (71, 97, 98). PGE is involved in control poly-ICLC show increased numbers of iM and iDC in the lungs, of intracellular Mtb replication but also prevents necrotic host cell −/− which are 10 times more permissive to Mtb infection than their death (99). In accordance, Ptgs2 mice, unable to produce PGE , counterparts in PBS-treated mice (72). Others confirmed that are more susceptible to Mtb infection than wild type mice, but to −/− signaling through IFNAR indeed augments the recruitment of a lesser degree than IL1 mice. Further, information on PGE in Mtb-permissive iM and iDC into the lungs (69). Mechanistically, TB is given in Box 2. IFNAR-dependent expression of the chemokine CCL2 mediates Type I interferons inhibit the expression and production of the influx of CCR2 monocytes that differentiate into iM and IL-1β and simultaneously increase the expression of 5-lipoxyge- iDC (72). Both myeloid and parenchymal cells can produce nase (5-LO), which is a competitive enzyme for COX2 in the ara- CCL2 in response to T1-IFNs, but parenchymal cells appear the chidonic acid metabolism (71, 90, 114, 115). As a result, IFNAR Frontiers in Immunology | www.frontiersin.org 6 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB expression and increase the expression of soluble antagonists for BOx 2 | The dual faces of prostaglandin e (Pge ) in tuberculosis (TB) 2 2 the IL-1 receptor (114, 132). immunity. Despite the abovementioned functional similarities between Prostaglandin E is generally considered a pro-inflammatory mediator and T1-IFNs and IFN-γ in IL-1β inhibition, mechanistic differences indispensable for the induction of fever, which is a hallmark symptom of active exist between these IFN types in mediating this effect. TB (100, 101). The anti-inflammatory effects of prostaglandin synthase (COX-) inhibitors such as NSAIDs underline this notion. However, high levels of PGE2 Ex vivo studies in human iM and iDC demonstrate that can also exert immunosuppressive effects as they stimulate alternative acti- IFN-β inhibits IL-1β production more potently than IFN-γ vation of macrophages (102), inhibit bactericidal activity (103), and promote (90, 114). One explanation might be that IFN-γ inhibits IL-10, production of IL-10 (104). Moreover, high PGE levels can stimulate the deve- while T1-IFNs induce IL-10, which contributes to the inhibition lopment of myeloid-derived suppressor cells with inhibitory effects on adaptive of IL-1β production (90, 114, 115). Additionally, an IL-10- immune cells (104, 105). Finally, PGE inhibits IL-12 production by DCs and IFN-γ production by T-cells, thereby promoting Th2/Th17 immunity (106, 107). independent inhibition of IL-1β by T1-IFNs was recently identi- In the serum and bronchoalveolar lavage fluid of TB patients, PGE levels fied (129). T1-IFNs induce cholesterol 25-hydroxylase, which were found to be elevated (71, 108, 109), and polymorphisms in the PGE2 potently reduces IL-1β transcription and broadly represses IL-1- receptor EP2 are associated with TB-susceptibility (110). Experimentally, one activating inflammasomes. In contrast, IFN-γ inhibits IL-1β mouse study showed that low PGE2 levels in the acute phase of infection by increasing intracellular nitric oxide in an iNOS-dependent are essential for iNOS-mediated control of Mtb (111). Also, PGE plays an important role during acute TB since the PGE2-producing enzyme COX2 way (120). This prevents NLRP3 inflammasome activation and competes for arachidonic acid substrate with 5-lipoxygenase, which produ- cleavage of pro-IL-1β into IL-1β. In contrast to the mechanisms ces leukotrienes and lipoxins. Hereby, PGE2 prevents necrotic cell death thus exerted by T1-IFNs, IFN-γ-induced iNOS not only limits benefiting the host (71). Opposed to the protective role of low PGE levels IL-1β-mediated inflammation but also markedly enhances the during acute disease, PGE2 levels are higher during the chronic phase of TB, and these concentrations contribute to disease by suppressing IFN-γ, bactericidal potential of iM (120). Conversely, T1-IFNs suppress TNF-α, and iNOS (111). Notably, the cellular source of PGE2 appears to differ iNOS production (90). Based on the stimulation of iNOS by between acute and chronic TB. During the acute phase of infection, inflam- IFN-γ and the inhibition of iNOS by T1-IFNs, it appears that matory myeloid cells are the main source of PGE2, while foamy macrophages iDC are more sensitive to T1-IFN signaling and iM to IFN-γ are strong producers of PGE during the chronic phase of disease (112). In when both types of interferon are present. T1-IFN-mediated line with a detrimental effect of high PGE2 levels in the chronic phase, foamy macrophages are typically associated with disease progression (113). inhibition of iNOS appears to occur primarily in iDC, since iDC −/− mice during viral infection, only expressed iNOS in IFNAR while iM appear more sensitive to IFN-γ and are the main source signaling causes a shift from COX2-mediated PGE production of iNOS in wild-type mice (131). to an increase in the 5-LO products such as lipoxin A (LXA ) When taken together, these data suggest that IL-1β inhibition 4 4 and leukotriene B (LTB ), which render cells more susceptible to by either T1-IFNs or IFN-γ has strong implications on the bacte- 4 4 necrotic cell death (71, 116). Pharmacological intervention in this ricidal potential of iM and iDC. Furthermore, T1-IFNs interfere process by administrating the 5-LO inhibitor Zileuton to Mtb- with the induction of iNOS by IFN-γ, particularly in iDC. This infected mice, improved disease outcomes during acute infection ts t fi he observation that IFN-γ only inhibits IL-1β production by −/− to similar extent as observed in IFNAR mice (71). An overview iM but not iDC in mouse TB models (90). Notably, iDC are the on the balance between IL-1β and T1-IFNs is given in Figure 2. most readily infected cells in the lungs of Mtb-infected mice (25) and are present in larger numbers than iM during Mtb infection 2.4.3. Prolonged IL-1β Signaling Causes PMN- (72, 133). Mediated Tissue Damage and Is Regulated by Both T1-IFNs and IFN-γ 2.4.4. The Interplay between T1-IFNs and IFN-γ e cr Th oss talk between T1-IFNs and IL-1β influences disease out- During direct contact with Mtb through TLRs, endogenous come in TB (71). However, this does not fully explain the harmful T1-IFN signaling through IRF3 promotes IL-12 production by effects of T1-IFNs observed in TB. Most importantly, although iDC over IL-23 (see also Figure  2; Box  3) (94, 134, 135). This IL-1β production is essential for protective immunity in the acute early IL-12 signaling is required to induce IFN-γ production by phase of disease in TB, it requires strict regulation as unchecked innate lymphoid cells (ILC) such as NK cells and possibly ILC1s IL-1β signaling in TB can result in excessive PMN-mediated tissue (136, 137). However, exogeneous T1-IFNs or T1-IFN signaling in damage (120, 123). Also, as explained in Box 2, IL-1β-mediated the absence of TLR stimulation can also inhibit IL-12 production PGE production is protective during acute disease but appears to by iDC (115, 138). This inhibition of IL-12 by T1-IFNs occurs have a detrimental effect during chronic disease. Finally, inflam- particularly through induction of IL-10 (15). T1-IFNs also inhibit matory mediators associated with continuing infection, e.g., the responsiveness of iDC to IFN-γ-mediated activation, which GM-CSF, predispose for IL-1β production over T1-IFNs by iM is required for Mtb killing. This occurs partially by reducing the and iDC (36, 94, 124–126). This reflects an increasing need over expression level of IFN-γ-receptor on the cell surface, but pri- high time to limit IL-1β-mediated inflammatory responses. regulatory phenotype in marily through induction of an IL-10 To prevent PMN-mediated inflammation caused by exces- which antimicrobial pathways by IFN-γ are not readily activated, as discussed below (90, 115, 131, 139–141). sive IL-1β signaling, the expression and production of IL-1β is inhibited not only by T1-IFNs but also by IFN-γ (90, 120). In Recent findings might explain the mechanism behind this paradox where T1-IFNs initially support IL-12-mediated IFN-γ line with this, both T1-IFNs and IFN-γ can inhibit PMN influx high (127–131). T1-IFNs and IFN-γ can both reduce pro-IL-1β gene production by NK cells but can also induce an IL-10 phenotype Frontiers in Immunology | www.frontiersin.org 7 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB FigURe 2 | inflammatory responses during acute infection in naïve inflammatory macrophages and dendritic cells. Green text indicates a beneficial host effect during Mtb infection and red indicates a detrimental effect. Mtb, Mycobacterium tuberculosis; PRR, pattern recognition receptor; STING, STimulator of INterferon Genes; TBK1, tank-binding kinase 1; IRF3, interferon regulatory factor 3; 5-LO, 5-lipoxygenase; COX-2, cyclooxygenase 2; PGE2, prostaglandin E2; EP2, 1 2 3 4 5 prostaglandin E receptor 2; ILC3, innate lymphoid cells type 3. Jayaraman et al. (97), Chen et al. (116), Shi et al. (107), Di Paolo et al. (98), Lockhart et al. (117), 6 7 8 9 10 11 12 13 Boniface et al. (106), El-Behi et al. (118), Fremond et al. (119), Mishra et al. (120), Watson et al. (81), Fleetwood et al. (94), Mayer-Barber et al. (71), Antonelli 14 15 16 17 18 et al. (72), Une et al. (121), Longhi et al. (122), Manca et al. (64), Manca et al. (65), and Mayer-Barber et al. (90). in iDC, which interferes with IL-12 production and prevents produce IFN-γ as early as 3 days post infection (154). This results high IFN-γ-mediated activation. It has been observed in different in a uniform presence of an IFN-γ-primed signature of Ly6C mouse models, including Mtb-infected mice, that T1-IFNs can monocytes in the circulation at day 6. Furthermore, IFN-γ indeed high only induce an IL-10 regulatory phenotype in monocyte- primed these monocytes toward a regulatory phenotype, as they derived DCs (iregDC) if these cells have been primed previously more effectively produced IL-10 in response to bacterial ligands by IFN-γ (43). IFN-γ-primed DCs that did not receive T1-IFN (154). We speculate that a similar mechanism of IFN-γ priming signaling differentiated into iDC that stimulated robust T-cell is likely to be involved in pulmonary infections. responses. This phenomenon of monocyte priming by IFN-γ has es Th e data suggest interplay between T1-IFNs and IFN-γ as been demonstrated to occur in the bone marrow (154). During proposed in Figure 3. T1-IFNs initially induce IFN-γ responses by gut infections, local production of IL-12 in mucosa-associated promoting IL-12 production in naïve cells as shown in Figure 2. lymphoid tissue stimulates bone-marrow-resident NK  cells to es Th e IL-12 responses stimulate IFN-γ production by ILC not Frontiers in Immunology | www.frontiersin.org 8 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB Next to their shared ability to inhibit IL-1β, an interesting BOx 3 | iL-12 or iL-23 production by dendritic cells? interplay between T1-IFNs and IFN-γ exists in TB as summarized IL-12 and IL-23 are heterodimeric cytokines composed of a common p40 in Figure  3. Two recent findings that are of particular interest subunit, coupled with either a p35 subunit in IL-12 or a p19 subunit in IL-23. high include the observation that T1-IFNs can only induce an IL-10 Both IL-12 and IL-23 are produced in particular by stimulated dendritic cells phenotype in IFN-γ-primed cells (43) and the inductive role of and to lesser degree by macrophages. The preferential production of IL-12 or IL-23 by these cells is multifactorial. Increased levels of PGE2 support T1-IFNs in early IL-12 signaling, which is required for IFN-γ IL-23 production over IL-12 (106, 107, 142). Activation of TLR2 and TLR4 priming in the bone marrow (154). Further, research into this also stimulates IL-23 production over IL-12, especially when NOD2 is simul- complex interplay between T1-IFNs and IFN-γ during early host taneously activated (143, 144). On the other hand, TLR9 and TLR3 agonists responses in TB would be highly interesting given the T1-IFN- preferentially induce IL-12 (135, 145, 146). Downstream of PRRs, activation of inducing capacities of Mtb and the shaping effect of early T1-IFN IRF 4 and 5 favor induction of IL-23, while IRF 1, 3, and 7 induce IL-12 (135, 147). In line with this, T1-IFN-mediated IRF3 activation and IFN-γ-mediated or IFN-γ signaling on the ensuing immune response. IRF-1-activation both favor IL-12 production (148, 149). IL-4 also favors IL-12 production and inhibits IL-23 production, especially 3. THe Th17 ReSPONSe iN TB in combination with IFN-γ or GM-CSF (150, 151). Finally, an important pathway that promotes IL-12 over IL-23 is ligation of the co-stimulatory molecule CD40 As discussed in the previous paragraph, T1-IFNs induce IL-12 by CD40L on activated T-cells or by agonist antibodies (152). Taken together, IL-23 is induced in the presence of pathogens and innate signaling in the production by iDC, while IL-1β induces IL-23. Other factors acute phase of infection, while onset of adaptive immunity with increased also influence production of IL-12 or IL-23 (see Box 3). IL-12 is levels of IFN-γ and/or IL-4 shifts the balance toward IL-12 (153). essential for the induction of IFN-γ responses in TB, but IL-1β is protective during acute TB despite inducing IL-23 over IL-12. Similar to the requirement of IL-12 for Th1 responses, IL-23 is only locally but also systemically, which results in IFN-γ priming essential for establishing Th17 immunity (157–159). Here, we of monocytes in the bone marrow. Once IFN-γ production is review the effect of IL-23 signaling and the Th17 response in TB. initiated, T1-IFNs mediate a regulatory function by inducing an high IL-10 phenotype in IFN-γ-primed iDC. This prevents further 3.1. introduction to the Th17 Response production of IL-12 by these cells, inhibits their activation by e Th Th17 response is distinct from classical cell-mediated Th1 IFN-γ, and results in an Mtb-permissive phenotype. immunity or B-cell-stimulating Th2 responses and is oen a ft sso- ciated with a potent inflammatory response and tissue damage 2.5. Summary: The Role of T1-iFNs in TB (159). Th17 cells display a high degree of plasticity and their abil- Several modest clinical successes have been shown with IFN-α ity to express signature markers of other T-helper lineages makes supplementation adjunct to antibiotic TB treatment (Table  1). it difficult to establish their exact role in disease. Four different However, case reports of TB reactivation under IFN-α treatment subsets of Th17  cells have been described to date with ranging without concomitant antibiotics have put T1-IFNs in a nega- inflammatory potential (160). On one side of the spectrum are tive spotlight (50–57). Furthermore, a T1-IFN transcriptional highly inflammatory and oen p ft athogenic IFN-γ/GM-CSF- signature in circulating leukocytes is associated with active TB. producing Th17.1 cells that result from prolonged IL-1β and Nevertheless, the functional role of T1-IFNs in TB patients IL-23 signaling (161). On the other side are IL-10-producing remains to be determined (62). Th17  cells, which can even transdifferentiate into regulatory Preclinical studies in mice support a detrimental role for T-cells and contribute to resolution of inflammation (162). T1-IFN in the acute phase of Mtb infection. T1-IFN signaling Despite the plasticity in cytokine production, IL-17 remains was associated with increased mortality in Mtb-susceptible mouse the hallmark cytokine of the Th17 response. Next to Th17 cells, strains and higher Mtb loads in the lungs in most studies (Table 2). γδ T-cells and ILC3 can also produce IL-17 in response to IL-23 However, it should be noted that most of these preclinical and IL-1β (27, 117, 163). IL-17 exerts its effects primarily on studies do not unequivocally support a harmful effect of T1-IFNs nearby parenchymal cells and to lesser extent on hematopoietic during the chronic phase of disease based on mortality, Mtb cells, which is distinct from Th1 and Th2 cytokines like IFN-γ and loads, or differences in adaptive immunity. IL-4 (159). In parenchymal cells, IL-17 primarily stimulates the In support of a pathogenic role of T1-IFNs during acute infec- production of the chemokines that attract PMN (164). However, tion, mycobacteria actively induce T1-IFNs by triggering cyto- it should be noted that IL-17 alone is a poor inducer of these solic PRRs. This leads to IFN-β production in an IRF3-dependent chemokines and that synergistic activation by inflammatory way. Subsequently, T1-IFNs mediate the CCL2/CCR2-dependent ligands such as IL-1β, TNF-α, or GM-CSF markedly increases migration of iM and iDC into the lungs (72). In these cells, inter- the effects of IL-17 (164, 165). ference of T1-IFNs with IL-1β and PGE as shown in Figure 2 can lead to an altered metabolism of arachidonic acids that leaves cells 3.2. The Th17 Response in Human TB more vulnerable to necrotic cell death (71). However, sustained infection IL-1β signaling itself carries the risk of excessive inflammation in TB and not only T1-IFNs but also IFN-γ inhibits IL-1β to prevent e exac Th t role of the Th17 response in human TB remains a topic of debate (13, 14, 166). Polymorphisms in genes encoding excessive PMN-mediated inflammation (120). T1-IFNs inhibit high IL-1β more effectively than IFN-γ but stimulate an IL-10 Mtb- IL-17 are associated with susceptibility to pulmonary TB, which indicates a role for this cytokine in TB (167–170). However, these permissive phenotype (72, 90). Frontiers in Immunology | www.frontiersin.org 9 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB FigURe 3 | Hypothetical interplay between type i interferons (T1-iFNs) and iFN-γ in monocyte priming and shaping of the immune response in Mtb infection. Dashed lines indicate speculations in the context of pulmonary Mtb infection; solid lines indicate shown pathways in human and/or in animal models. (1) T1-IFN induces migration of CCR2 monocytes (iMo) from the bone marrow to the lungs of Mtb-infected mice under influence of CCL2 (72). Locally, these cells + high + int develop into CD11b Ly6C inflammatory macrophages (iM) and CD11b Ly6C inflammatory dendritic cells (iDC) (43). (2) As shown in Figure 1, naïve iM and iDC can initiate either IL-1β-mediated inflammation or T1-IFN-mediated inflammation. Mtb actively triggers intracellular pattern recognition receptors to induce a T1-IFN-mediated response. (3) Additionally, iM and iDC in the naïve situation have differentiated under influence of M-CSF, which makes them more responsive to T1-IFN signaling (94). During progression of Mtb infection, GM-CSF levels rise and increase the potential for IL-1β production by iM and iDC (94, 125, 155, 156). (4) Similar to the situation in gut infection, we propose that in tuberculosis (TB) IL-12 production in the lungs stimulates IFN-γ production by bone-marrow-resident NK cells, which locally primes monocytes (154). IFN-γ priming of monocyte-derived iDC is necessary for T1-IFNs to induce a regulatory (iregDC) phenotype in iDC in the lungs (43). (5) Additionally, IFN-γ stimulates monopoiesis over granulopoiesis by granulocyte/macrophage progenitor cells (128). (6) As Mtb infection progresses and GM-CSF levels increase, iM and iDC readily produce IL-1β [see also (3)] (124, 155), which can lead to PMN-mediated inflammatory damage in TB (120). (7) IL-1β production can be inhibited in response to either IFN-γ or IFN-β through mechanistically distinct pathways that differently affect Mtb killing. (8) Signaling through IFN-α/β receptor in IFN-γ-primed iDCs induces IL-10 production (43, 115, 131), inhibits IL-12 production (115), and makes these cells unresponsive to activation by IFN-γ (43, 115, 141), which together interfere with protective immunity during acute Mtb infection. findings could not be reproduced in different demographic set- Different studies report PBMC stimulation assays with Mtb- tings (171, 172). specific antigens showing either increased or reduced Th17 Analyses of Th17 responses in peripheral blood mononuclear responses in ATB compared to LTBI (Table  3). es Th e diverse cells (PBMC) from TB patients do not show uniform results either. findings are similar to those observed in IFN-γ response assays Direct ex vivo analyses of unstimulated circulating CD4 T-cells (IGRA), in which the levels of IFN-γ oen a ft lso cannot discrimi- show that active TB (ATB) is associated with reduced frequencies nate between ATB and LTBI (176, 177). Interestingly, both Th1 of circulating Th17 cells compared to latent TB infection (LTBI) and Th17 cells appear functionally inhibited in ATB patients by a (173, 174). However, serum IL-17 levels do not differ between PD-1-mediated immunosuppressive state (178–181). In accord, ATB and LTBI, and IL-17 is undetectable in the bronchoalveolar reductions in PD-1 expression under TB treatment restored both lavage fluid during both stages of disease (174, 175). Th1 and Th17 responses (182). Frontiers in Immunology | www.frontiersin.org 10 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB TABLe 3 | iL-17 responses in patients with active TB (ATB) compared to This tendency of Th17 cells to produce IFN-γ instead of IL-17 latent tuberculosis infection (LTBi). during recall responses might explain the observation that IL-17 production during later phases of Mtb infection is dominated by increased in ATB No difference Reduced in ATB γδ T-cells rather than CD4 cells (117, 198). + + % of IL-17 CD4 T-cells When taken together, initial shaping of the local inflamma- Short Basile et al. (183) Marin et al. (184, Scriba et al. (175); tory environment by IL-17 and IL-23 during acute infection incubation 185) Perreau et al. (186) stimulates local TLS formation. This facilitates the development (0–48 h) of more robust Th1 responses by improving contact between Long Jurado et al. (187); Cowan et al. (174); Perreau et al. (186); antigen-presenting cells (APC) and lymphoid cells (Figure  4). incubation Marin et al. (184) Marin et al. (185) Heidarnezhad et al. Furthermore, Th17 cells confer protective immunity during recall (72–144 h) (188) responses by their enhanced capacity to migrate to the lungs and Ex vivo IL-17 Jurado et al. (187); Sargentini et al. Kumar et al. (192); responses compared to other CD4 T-helper cell stimulate Tfh production Xu et al. (189) (190); Cowan et al. Nunnari et al. (193); populations. (174); Kim et al. Bandaru et al. (182) (191) Only in MDR-TB. 3.4. The Th17 Response, PMN, and inflammatory Damage Taken together, systemic Th17 responses in TB patients dem- IL-17 stimulates granulopoiesis in the bone marrow and increases onstrate similar variability as observed for IGRA studies. Both PMN influx to the site of infection by inducing G-CSF, CXCL1, are unable to distinguish ATB from LTBI. How these systemic CXCL3, and CXCL5 expression by parenchymal cells in mice responses relate to local host responses in the lungs has not been or G-CSF and IL-8 in humans (159). These effects of IL-17 are characterized in TB patients. markedly enhanced through synergistic activation by inflamma- tory mediators such as IL-1β, TNF-α, or GM-CSF (164, 212, 213). 3.3. Preclinical Studies in Mice Support a In this regard, IL-17 is not a strong inducer of inflammation by Protective Role for iL-23 and iL-17 in TB itself, but rather amplifies preexisting inflammation. This IL-17- Based on mortality and mycobacterial loads, studies in Mtb- mediated “inflammatory boost” can positively shape adaptive infected mice support a protective role for IL-23 and IL-17 in TB, immunity, but prolonged or repeated antigen exposure can also but only during later stages of disease (Table 4). lead to PMN-mediated pathological inflammation (214). Since Interestingly, these late protective effects result from effects IL-17 signaling is inevitably linked to PMN influx, the role of induced during the initial phase infection (142, 195). This is due PMN in TB provides an additional perspective on the effects of to the essential roles of IL-23 and IL-17 in the local formation of IL-17 signaling in TB. tertiary lymphoid structures (TLS) (199, 200). es Th e structures are Review of available literature on the role of PMN in TB yields a formed during early infection but can persist for longer periods of complex picture with seemingly conflicting effects (14, 166, 215). time and are associated with protective immunity in Mtb-infected In patients with active TB, PMN are the predominantly infected mice (199, 201) (Table 4; Figure 4). Furthermore, IL-17 and IL-23 cells in the airways and provide a permissive site for a burst of increase the expression of the chemokine CXCL13 (194, 197). active mycobacterial replication prior to transmission (216). On This chemokine stimulates the influx of TLS-associated CXCR5 the other hand, PMN from healthy individuals, especially when follicular helper (T )-cell, which facilitate optimal localization of fh stimulated with TNF-α, show a strong bactericidal effect (217). effector T-cell populations within the lung parenchyma, thereby In preclinical TB models, highly susceptible mouse strains such promoting efficient T-cell-dependent macrophage activation and as I/St, CBA/J, or DBA/2 show an enhanced influx of apoptosis- intracellular Mtb killing (194, 201). resistant, highly phagocytic neutrophils that negatively aeff ct On account of their ability to induce TLS formation, boosting survival compared to more TB-resistant C57BL/6 and BALB/c IL-23 and IL-17 production is also an interesting strategy for mice (218–220). Moreover, PMN are poor producers of essential vaccine-induced protection against TB. In this regard, IL-17 pro- cytokines such as IL-1α/β and IL-12p40 in the anti-TB response duction by Th17 cells during recall responses is indeed dependent (90, 221). These effects in preclinical models primarily suggest on IL-23 and could reduce mycobacterial loads in the lungs of a negative contribution of PMN to acute disease. However, Mtb-infected mice (210). Th17 cells preferentially migrate to the increasing evidence suggests a supportive role for PMN in pro- lungs and are better contained in the lungs compared to Th1 cells tective immunity. PMN can indirectly augment IL-1β-mediated upon adoptive transfer to naïve mice (210, 211). The develop- inflammatory responses in macrophages aer co ft ntact with Mtb mental flexibility of Th17 cells is illustrated in experiments where (202, 204, 205). Also, and consistent with Th17 responses, PMN Mtb-antigen-primed Th17 cells have been adoptively transferred play an essential role in generation of protective recall responses to naïve mice (210). Initially, these Th17  cells produce IL-17. in Mtb-infected mice (195, 206, 222). Early, but not late PMN However, upon recall immunity against Mtb, they primarily pro- recruitment is essential for IL-17-mediated long-term control of duce IFN-γ, with or without IL-17. Paradoxically, the latter switch Mtb infection (195). This can be explained by the finding that results in a less effective reduction in bacterial loads compared to DCs that acquire Mtb through uptake of infected PMN are better IL-17-producing Th17 cells that are adoptively transferred from able to activate T-cells (203, 222). The importance of this mecha- −/− IFN-γ mice. nism is recently highlighted in Mtb-infected mice, showing that Frontiers in Immunology | www.frontiersin.org 11 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB TABLe 4 | Th17-related effects in preclinical tuberculosis (TB) studies in mice. Mice intervention Mtb strain, route Survival Mtb load (vs. wild-type mice) immunological effect Reference (age, weeks) B6 (6–12) IL23 H37Rv (100 CFU), No data No difference in lungs No IL-17-producing cells in lungs up Khader et al. (158) −/− p19 aerosol 1 log higher Mtb load in spleen at to day 150 day 150 B6 (6–12) IL23 H37Rv (100 CFU), No data Day 120 and onward, 0.5–1 log Reduced no. of B-cell follicles at day Khader et al. (194) −/− p19 aerosol higher Mtb load in lungs 200 (Cxcl13 mediated) Strongly impaired IL-17, IL-22 production in lungs up to day 250 −/− B6 (6–12) IL22 H37Rv (100 CFU), No data No effect up to day 200 Suboptimal B-cell follicle development Khader et al. (194) aerosol (Cxcl13-mediated) B6 (6–9) IL-17 H37Rv Higher 1.5 log higher Mtb load at week 12 Impaired cell recruitment (PMN, Freches et al. (195) −/− 3  RA (1.10 CFU), i.t. mortality and week 20 in lungs lymphocytes, Mo/DC) (median Increased IL-1β survival: 18 Decreased TNF-α, IL-6 and IL-10 vs. 35 weeks) B6 (6–12) IL-17 H37Rv (100 CFU), No data No effect up to day 200 Suboptimal B-cell follicle development Khader et al. (194) −/− RA aerosol (Cxcl13-mediated) −/− B6 (8–12) IL-17 H37Rv No data 1.5 log higher Mtb load Reduced no. of granulomas at day 28 Okamoto Yoshida (1.10  CFU), i.t. et al. (196) −/− B6 (6–8) IL-17 HN878 (100 CFU), No data 1 log higher Mtb load in lungs at Infection with HN878 showed robust Gopal et al. (197) aerosol day 30 production of IL-1β through TLR2, 0.5 log higher Mtb load in lungs at which supported increased IL-17 day 60 production compared to H37Rv and CDC1551 −/− B6 (6–8) IL-17 H37Rv, CDC1551 No data No difference at day 30 and day 60 Gopal et al. (197) (100 CFU), aerosol −/− B6 (8–12) IL-17 H37Rv Higher 1.5 log higher Mtb loads in lungs at Impaired granuloma formation, γδ Umemura et al. (198) 3  (1.10 CFU), i.t. mortality day 30, 1 log higher Mtb loads at day T-cells primary source of IL-17 60 and day 120 Red text indicates a harmful effect to the host; CFU, colony forming units; IL-17RA, IL-17 receptor A; i.t., intratracheal instillation. PMN-depletion during vaccination prevented the generation of of recall responses, or initiate resolution of inflammation in the specific Th1 and Th17 responses (206). absence of inflammatory or microbial stimuli. A second emerging protective role of PMN is their contribu- tion to initiating inflammation resolution (223). In mouse TB 3.5. Summary: The Role of Th17 models, PMN are the main producers of IL-10 in the lungs and can dampen inflammatory damage (224). In this regulatory role, immunity in TB PMN inhibit Th17 responses but do not interfere with IFN-γ- e r Th oles of IL-23 and IL-17 in TB are more subtle than the effects of Th1-related cytokines or T1-IFNs. Patient data are mostly lim- mediated Th1 immunity due to relative insensitivity of Th1 cells to IL-10 (224, 225). Another regulatory effect of PMN concerns ited to studies in PBMC. These show inconclusive results that are possibly confounded by the dynamics and heterogeneity of the their apoptosis and subsequent phagocytosis by macrophages in the absence of extracellular Mtb. This inhibits IL-23 production Th17 response, which can range from highly pro-inflammatory high M2c IFN-γ/GM-CSF-producing Th17.1 cells to IL-10-producing by these macrophages and induces a regulatory IL-10 phenotype under influence of IL-17 and IL-10 (see Figure 4) (226, regulatory Th17 cells. 227). IL-17 can further contribute to this process by attenuating Preclinical mouse TB models provide evidence for a protective the anti-apoptotic effect of GM-CSF on PMN and by stimulating role of the Th17 cytokines IL-23 and IL-17 in TB. These protec- PMN apoptosis (228, 229). tive effects become apparent in the chronic phase of infection Taken together, PMN recruitment to the site of infection but result from IL-23/IL-17-mediated effects in the earlier, acute is largely dependent on IL-17, but only in synergy with innate phase of infection. This is associated with early protective effects inflammatory cytokines such as IL-1β. Locally, these recruited of IL-1β, which is a strong inducer of IL-23 and IL-17 (Figure 4). PMN contribute to inflammation if pathogens are still present, Mechanistically, evidence for the protective effects of IL-17 and improve dendritic cell function, and contribute to the formation IL-23 primarily points toward their role in the development of Frontiers in Immunology | www.frontiersin.org 12 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB FigURe 4 | The iL-23/iL-17 axis in acute tuberculosis. (1) When inflammatory dendritic cells (iDC) recognize Mtb through membrane-bound toll-like receptors, they can secrete IL-1β, IL-23, and prostaglandin E2 (PGE ) (see Figure 1). This occurs more efficiently if iDC are activated through contact with Mtb-infected PMN, which also stimulates their migratory capacity to tertiary lymphoid structures (TLS) and promotes recall immunity (202–206). (2) The combination of IL-1β and IL-23 induces IL-17 production by γδ T-cells and possibly ILC3 (27, 117). (3) Activation of parenchymal cells by IL-17 in combination with IL-1β or other inflammatory mediators ultimately results in PMN influx. (4) PMN contribute to inflammation when stimulated by extracellular Mtb or inflammatory cytokines. (5) Activated PMN readily cause tissue damage through production of ROS and proteases; this effect is suppressed by activated iDC in a PGE -dependent way (112, 207, 208). (6) IL-23 and IL-17 stimulate the local production of CXCL13 by stromal cells (194, 199). This promotes TLS formation and follicular helper T-cell migration to the site of infection. (7) CD40 ligation in the interaction between (i)DC and CD4 T-cells is a strong stimulus for IL-12 production over IL-23 (Box 3) and leads to Th1 formation and IFN-γ production. (8) IFN-γ inhibits IL-1β production and shifts IL-23 production to IL-12, thus inhibiting IL-17 production and reinforcing the Th1 response (209). (9) In the absence of inflammatory stimuli, PMN can produce IL-10 and undergo apoptosis. Phagocytosis of apoptotic PMN induces an IL-10-producing regulatory M2c phenotype in macrophages and further contributes to resolution of inflammation. TLS during the acute phase of disease, which provides protective cells to protective immunity in TB is increasingly recognized effects during later stages (199, 230). Additionally, IL-23 and (206). Early, but not late PMN recruitment is essential for IL-17- IL-17 induce CXCL13 expression that mediates the influx of mediated long-term control of Mtb infection (195) and DCs that TLS-associated T cells. TLS and T responses facilitate optimal acquire Mtb through uptake of infected PMN are better able to fh fh interactions between adaptive and innate immunity, contribute activate T-cells than DCs that directly interact with Mtb them- to granuloma formation, and improve the quality of T-cell recall selves (203, 222). The ability of IL-17 to induce the production responses in TB (201). In TB patients, TLS have also been associ- of PMN-attracting chemokines in parenchymal cells is markedly ated with immune control, but more in-depth research is needed improved when IL-17 signals in synergy with inflammatory to establish their exact functional role and contribution to protec- mediators such as IL-1β, which again indicates synergy between tive immunity (201). IL-1β and IL-17 responses during acute TB. Prolonged activation Next to TLS formation and function, IL-23 and IL-17 mediate of IL-1β and IL-17 responses can lead to massive accumulation the influx of PMN into the lungs and the contribution of these of PMN, and their local necrotic death can also be damaging to Frontiers in Immunology | www.frontiersin.org 13 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB the host. However, in the absence of inflammatory stimuli, PMN In accordance, pDC have been found to be a major source of are an important source of IL-10 in the lungs and can initiate T1-IFNs in SLE (247, 248). Immune complexes (IC), consisting resolution of inflammation (Figure 4). of antibodies bound to self-DNA, are a major trigger for IFN-α production by pDC in AID (249). However, pDC are not acti- vated by self-DNA under steady state conditions, which indicates 4. T1-iFNs, THe Th17 ReSPONSe AND that additional stimuli are required. One such stimulus is the THeiR iNTeRACTiONS iN AUTOiMMUNe PMN-derived antimicrobial peptide LL37 (249), which convert DiSeASe inert self-DNA into a potent activator of endosomal TLR9 (250). Another stimulus is the nuclear protein high mobility group box Autoimmune diseases comprise a wide range of organ-specific 1 (HMGB1) protein, which is secreted by activated myeloid cells and systemic disorders. Most systemic AID are considered clas- and passively released by necrotic, but not apoptotic cells (251). sical B cell-mediated diseases, typified by circulating autoreactive HMGB1 binds DNA, and the formed complexes bind with high antibodies against intracellular self-antigens. The clinical presen- affinity to receptor for advanced glycation end-products, which tation of different AID varies, but evidence from genome-wide facilitates internalization into the endosome where TLR9 can be association studies points toward common immunogenetic activated (249). Extracellular HMGB1 also triggers the recruit- mechanisms, as many systemic AID share disease-associated ment of PMN and stimulates their formation of neutrophil genes (231). Another trait particularly shared amongst different extracellular traps (NETs) (252). NETs contain large amounts of antibody-driven AID is the expression of a T1-IFN signature in nucleic acids and LL37 and are also a major driving factor behind both blood- and disease-ae ff cted tissue (232–234), the strength chronic pDC activation and IFN-α production in SLE (253). of which generally correlates with disease activity and severity It deserves mention that NET formation is driven by reactive (235–238). Vice versa, T1-IFN immunotherapy as treatment oxygen species (ROS), which in PMN are particularly produced for other diseases is known to cause symptoms similar to those by NADPH oxidase and subsequently processed by myeloper- observed in AID, such as development of psoriatic lesions in MS oxidase (254). Paradoxically, despite the capacity of NETs to or hepatitis C-infected patients (239, 240). induce T1-IFNs and the pathogenic role of T1-IFNs in SLE, T-cells also have a major impact on the development and NADPH oxidase appears to be protective in SLE (255). Lupus- progression of AID and increasing evidence points toward prone mice deficient in NADPH-oxidase develop more severe crucial involvement of the Th17 response in the pathogenesis SLE (255). Moreover, autoimmunity with T1-IFN signatures can of multiple AID (160, 241). Th17  cells have been shown to be still develop in individuals with chronic granulomatous disease, critical in the pathogenesis of MS and rheumatoid arthritis (RA) who lack NADPH-oxidase activity (256). This seeming con- (19, 160). However, Th17  cells have also been associated with tradiction has been partially explained by the observation that disease severity in AID characterized by a T1-IFN signature, such IgG autoantibody-mediated NETosis, which is most relevant in as systemic lupus erythematosus (SLE) (20, 233, 242, 243). Since SLE, is specifically reliant on mitochondrial ROS, while NETosis T1-IFN signatures and Th17 responses are both associated with induced by, e.g., TLR4 signaling is NADPH dependent (256). disease in AID, the question arises whether these two pathways In line with this, NETs from SLE patients have been shown to act in concert to sustain and amplify autoimmune responses, contain mitochondrial DNA (256). Thus, the way NETs are or control each other (20, 21, 244). Therefore, we will discuss induced, and the type of DNA that is present on NETs probably below the involvement of the T1-IFN and Th17 responses in AID also influences their ability to induce T1-IFNs and their role in individually as well as their interaction. We refer readers who are disease. familiar with the contributions of T1-IFN and Th17 in AID to Taken together, TLR9-mediated IFN-α production by pDC in continue at Section 4.3 where we discuss the interaction between response to IC and NETs appears the major driving factor behind these pathways. T1-IFN production in autoantibody-mediated AID. Additionally, the way NETs are induced and the type of DNA present on NETs 4.1. The Contribution of T1-iFNs to the can influence disease outcomes. Pathogenesis of AiD Most insight into the role of T1-IFNs in the pathogenesis of AID 4.1.2. Disease-Promoting Effects of T1-IFN in AID has been obtained in SLE, which was the first disease in which Type I interferons exert a detrimental effect in AID through dif- a T1-IFN transcriptional signature was identified in 2003 (235). ferent pathways. In monocyte-derived cells, T1-IFNs stimulate Since then it has become clear that 60–80% of adult SLE patients maturation, increase phagocytic capacities (257), and increase and nearly 100% of pediatric SLE patients express a T1-IFN sig- the expression of co-stimulatory molecules (258). Also, T1-IFNs nature in their blood (245). Several mechanisms through which have a direct stimulating effect on T-cells. Together, these effects T1-IFNs contribute to disease in SLE, outlined below, have been promote the generation of autoreactive T-cells, which support elucidated. autoreactive B-cell responses (257, 259). At cytokine level, T1-IFNs can induce the production of B-cell 4.1.1. Induction of T1-IFNs in AID activating factor (BAFF) by myeloid cells (238, 260, 261). BAFF Specifically IFN-α appears to play a central role in SLE pathogen- induction confers a significant proportion of T1-IFN-mediated esis (245, 246). As mentioned in Section 2.3 IFN-α is produced damage in SLE as supported by the observation that IFN-α in an IRF7-dependent way by pDC and other myeloid cell types. administration induces disease in SLE-prone mice but fails to Frontiers in Immunology | www.frontiersin.org 14 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB do so in B-cell-deficient and BAFF-deficient mice on the same Th17.1 cells (161). These cells can also switch their chemokine + + background (262). BAFF plays a central role in the development receptor profile and become CCR2 instead of CCR6 (161). and selection of autoreactive B-cells (260). In line with this, Expression of CCR2 by Th17.1 cells can contribute to their increased BAFF expression correlates with disease severity in inflammatory potential as it can divert their migration to sites SLE (21, 260, 263). BAFF also induces class switch recombina- without concomitant influx of regulatory T-cells, which depend tion in B-cells, leading to preferential expression of IgG and IgA on CCR6 for their migration (278). over IgM, which is important for Fc-receptor-mediated NETosis Mechanistically, it was shown in a mouse EAE model that induction in PMN (264). The clinical relevance of BAFF in SLE GM-CSF exerted its pathogenic effector function by stimulating pathogenesis is illustrated by the current use of belimumab, a IL-1β production by monocyte-derived cells (279). This suggests monoclonal antibody against BAFF, as treatment for SLE (265). a positive inflammatory feedback loop, since IL-1β in turn pro- Interestingly, targeting BAFF is effective in SLE patients, while motes IL-23 production and development of Th17.1 cells (118). B-cell depleting therapies using CD-20-targeting rituximab show A similar pathogenic Th17.1 response is observed in RA, which disappointing results in phase III clinical trials (266, 267). This was the first AID in which IL-1β inhibition was approved for suggests effector functions of BAFF other than B-cell activation. clinical use (280). Also, regarding the distinction between Th17 In this regard, BAFF can act as a co-stimulatory molecule for and Th17.1 responses in RA, it should be noted that anti-GM-CSF T-cells and promote Th17 development (268, 269). BAFF can therapy shows more promise than anti-IL-17 in clinical phase I/ also directly activate plasma cells, which are not depleted by II trials (160, 281). rituximab (270, 271). 4.2.2. The Contribution of IL-17-Producing Th17 Cells to AID Pathogenesis 4.2. The Contribution of Th17 in the Next to GM-CSF-secreting Th17.1 cells, regular IL-17-producing Pathogenesis of AiD Th17 cells also have been identified as pathogenic in other AID. 4.2.1. GM-CSF-Secreting Th17.1 Cells This is best exemplified by the clinical successes of targeting Pathogenic effects of Th17-mediated immunity in AID have IL-17 in psoriasis (282). Th17-associated pathogenic effects in been studied most detailed in MS and RA and their respective SLE also appear to be driven by IL-17 rather than GM-CSF (21, mouse models, experimental autoimmune encephalitis (EAE), 283). This is further supported by the specific contribution of and collagen-induced arthritis (160, 242). MS was long believed PMN to disease in SLE, which is dependent on IL-17, opposed to to be primarily driven by an IL-12/Th1 response, but this concept GM-CSF that primarily influences the inflammatory potential of was challenged by observations in the EAE mouse model for monocytes in MS and RA. MS showing that the IL-23p19 subunit instead of IL-12p35 (see Box  3) caused disease (272). In addition, the classic cytokines 4.3. interactions between T1-iFNs and the of Th1 and Th17 immunity, i.e., IFN-γ and IL-17, respectively, Th17 Response in AiD were found dispensable in EAE and instead GM-CSF appeared Systemic lupus erythematosus and other autoantibody-mediated to be the effector cytokine responsible for IL-23-induced AID show a pathogenic role for T1-IFNs, while T-cell-mediated encephalopathy (118). Notably, while most studies agree on a AID, such as MS, are driven primarily by GM-CSF-stimulated central pathogenic role for GM-CSF in MS, conflicting results are IL-1β production. With the functional dichotomy of IL-1β and reported regarding its cellular source (19, 273–275). One study T1-IFNs in mind, as shown in Figure 2, MS and SLE seem to be shows that GM-CSF expression in MS patients is promoted by opposite ends of the disease spectrum in AID instead of dem- the IL-12/T-bet/Th1 axis, instead of IL-23 as observed in mouse onstrating interactions between T1-IFNs and the Th17 response. EAE (273). Other publications report that B-cells are a major However, the existence of different Th17 subsets might explain source of GM-CSF and specifically act in concert with Th17 cells this seeming disparity and suggest roles for GM-CSF-producing (274, 276). In accord with these discrepant results, MS is shown Th17.1 cells in MS and regular IL-17-producing Th17 cells in SLE. to be a heterogeneous disease that can be driven by either Th1 or Both Th17 responses interact differently with T1-IFNs as will be Th17 immunity (242), which also has implications for therapy as discussed here. We identify three relevant interactions: (1) Th17.1 will be discussed in Section 4.3.1. responses are fueled by T1-IFN-stimulated influx of CCR2 One interesting observation in this regard is the development inflammatory monocytes; (2) a pathological IL-17/T1-IFN/BAFF of “hybrid” Th17.1 cells that express markers of both Th17 cells axis driven by NET-forming PMN; and (3) Th17 immunity and T-cells in both mice and man do not and Th1 cells. Naïve CD4 + T1-IFNs collaborate in the generation and function of TLS. An express the IL-23 receptor and can either differentiate into T-bet overview of these pathways is presented in Figure 5. Th1  cells under influence of IL-12 or differentiate into CCR6 Th17 cells under influence of IL-6 and TGF-β (161). These IL-6/ TGF-β-differentiated Th17 cells have low inflammatory potential 4.3.1. T1-IFNs Can Contribute to and are prone to adopt an IL-10-producing regulatory phenotype. Th17.1-Mediated AID However, IL-6 also induces STAT3-dependent upregulation of Among MS patients treated with IFN-β, approximately IL-23 receptor (277). Subsequent (re)activation of such IL-6- 30–50% do  not respond favorably to treatment (284). It was shown that IFN-β suppresses Th1-mediated inflammation in primed Th17 cells by IL-23 increases Th1-associated T-bet expres- sion and generates inflammatory IFN-γ/GM-CSF-producing MS but is ineffective  and may even exacerbate Th17-mediated Frontiers in Immunology | www.frontiersin.org 15 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB FigURe 5 | interactions between type i interferons (T1-iFNs) and Th17 immunity in autoimmune diseases. The color grading in the figure indicates the level of involvement of either Th17 immunity or T1-IFN-associated signaling. (1) T1-IFNs, primarily produced by plasmacytoid dendritic (pDC) but also by inflammatory dendritic cells (iDC) and PMN, prime the latter cells toward a T1-IFN/B-cell activating factor (BAFF)-producing phenotype, promote NETosis by PMN and stimulate monocyte migration by inducing CCL2 production. (2) BAFF activates B-cells, stimulates tertiary lymphoid structures (TLS) formation together with CXCL13, directly promotes Th17 differentiation (not shown), and stimulates the release of IL-1β by iDC. (3) TLS facilitate optimal interaction between activated B-cells and antigen-presenting cells (APC), while necrosis, neutrophil extracellular traps, and T1-IFN increase the chance that these APC present self-antigens. Subsequent germinal center (GC) reactions within these TLS result in B-cells differentiating into plasma cells that produce large quantities of autoantibodies. These autoantibodies can mediate tissue damage and sustain a self-amplifying loop by inducing NETosis through binding the Fc-receptor on PMN. B-cells can also contribute to Th17 immunity by their ability to secrete IL-6 and GM-CSF (not shown and uncertain if this is BAFF dependent). (4) NETs trap antibodies. This facilitates their Fc-receptor-mediated internalization by pDC in which they stimulate T1-IFN production through endosomal TLR9 activation. Circulating NETs also stimulate IL-1β production by iDC and can mediate tissue damage. (5) In a pro-inflammatory feedback loop, IL-23 stimulates the development of GM-CSF- producing Th17 cells (Th17.1), which in turn, together with BAFF and/or NETs stimulate an inflammatory phenotype in iDC. (6) IL-1β and IL-23 stimulate IL-17 production by γδ T-cells, while concomitant stimulation with IL-1β and TNF-α is required for IL-17-induced G-CSF and chemokine production in parenchymal cells. (7) IL-1β and TNF-α activate PMN to release reactive oxygen species (ROS) and proteases that cause tissue damage. Furthermore, GM-CSF increases longevity of PMN (not shown). Finally, the priming of PMN and monocytes prior to entering the site of disease is important for their eventual effector function. For monocytes this is shown in more detail in Figure 3. u Th s, a strongly pro-inflammatory condition is created in Th17.1- inflammation  (19). This  is one of the first studies that report a mediated MS. Since regulatory T  lymphocytes rely on CCR6 detrimental interaction between T1-IFNs and Th17 responses. rather than CCR2 (279), recruitment of these anti-inflammatory Given the importance of Th17.1 cells in MS, this negative outcome cells does not appear to hold pace with the influx of inflammatory might be explained by the observation that IFN-β therapy in MS monocytes and Th17.1 cells in MS. increases CCL2 production (285). Expression of this chemokine in the brain recruits inflammatory CCR2 monocytes as well as Th17.1 cells, which switch their chemokine receptor profile from 4.3.2. A Pathological IL-17/T1-IFNs/BAFF Axis in AID + + CCR6 to CCR2 upon terminal differentiation (161). Moreover, IL-17 induces PMN influx through induction of G-CSF and Th17.1 cells stimulate IL-1β production in CCR2 monocytes chemokines (see Section 3.4), which contribute to the produc- (279, 286). Inflammatory monocytes may differentiate locally tion of IFN-α by pDC via the NETosis process (see Section 4.1.1). into dendritic cells further stimulating Th17 responses (287). However, increasing evidence suggests a more prominent Frontiers in Immunology | www.frontiersin.org 16 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB contribution of IL-17 and PMN to T1-IFN-mediated disease in inflammation. An overview of these interacting pathways is shown in Figure 5. SLE. First, besides being major inducers of IFN-α production by pDC upon NETosis, PMN also appear to be a significant source of IFN-α themselves (288, 289). This was related to their sheer num- 5. iNTeRACTiONS BeTweeN T1-iFNs AND bers, as circulating pDC were 27 times more efficient in secreting Th17 iMMUNiTY iN TB IFN-α, but PMN were 100 times more frequent (289). Second, both T1-IFNs and IL-17-induced G-CSF prime PMN for NETosis In the previous section, we have outlined how T1-IFNs and (250, 290). In accord, circulating PMN of SLE patients are also the Th17 immunity interact in AID (illustrated in Figure  5). These main cells expressing the transcriptional T1-IFN signature and interactions primarily concern (1) Th17.1 responses fueled by release more NETs than PMN from healthy individuals (250, 253, T1-IFN-stimulated influx of CCR2 monocytes; (2) The IL-17/ 288, 289, 291, 292). Thirdly, T1-IFNs stimulate BAFF produc- T1-IFNs/BAFF axis driven by NET-forming PMN; and (3) syn- tion, which is essential for T1-IFN-mediated pathogenic effects ergism between Th17 immunity and T1-IFNs in TLS formation in mouse SLE (261, 262, 293). It is recently shown that IL-17 and function. In this section, we assess the relevance of these also induces BAFF production and that IL-17-driven, G-CSF- three pathways in TB based on cell types and effector molecules dependent PMN recruitment drives plasma cell responses during involved. Each subsection contains a part of Figure  5, supple- emergency granulopoiesis in a BAFF-dependent way (271). Also, mented with relevant finding and outstanding questions in TB. therapeutically administered G-CSF, which is physiologically induced by IL-17, increases BAFF production by PMN (294). 5.1. Th17.1 Responses in TB es Th e interactions indicate a prominent role for IL-17- Studies in MS and RA emphasize the difference between GM-CSF/ mediated PMN influx in T1-IFN-production and induction in IFN-γ-producing Th17.1 cells and regular IL-17-producing AID and synergistic induction of BAFF production by IL-17 and Th17  cells. e f Th ormer primarily increase the inflammatory T1-IFNs. In support of this, IL-17 and Th17 cells are associated potential of monocytes (Figure  6), while the latter are more with disease severity in SLE to similar extent as T1-IFNs (20, closely associated with PMN. Data on subtypes of Th17 cells and 21, 241, 244). In turn, BAFF can promote Th17 responses (268, particularly Th17.1 cells in human TB are limited. One study 269). This further suggests an inflammatory loop with a central shows that circulating GM-CSF T-cells are not increased in ATB role for PMN in which IL-17, T1-IFNs, and BAFF continuously compared to LTBI, but it is unclear if this concerns Th17.1 cells increase each other’s production and contribute to autoantibody- or Th1  cells (309). Interestingly, GM-CSF production by both mediated responses. granuloma-associated T-cells and circulating CD4 T-cells in TB patients only occurs aer m ft ycobacterial antigen stimulation 4.3.3. T1-IFNs, Th17 Responses, and TLS in AID (309, 310). In mice, adoptively transferred Mtb-primed Th17 cells Finally, T1-IFNs and Th17 responses converge onto the develop- ment and functioning of TLS. In these structures, T cells support fh germinal center (GC) reactions in which B-cells differentiate into antibody-producing plasma cells and memory cells (295). As expected from their function, TLS and T cells are essential com- fh ponents in the pathogenesis of multiple autoantibody-mediated AID (296–303). The cytokines IL-17 and IL-22 secreted by ILC3, γδ T-cells and Th17  cells are required for local TLS formation (199, 230, 304). T1-IFN- and IL-17-induced BAFF promote the formation and integrity of GCs within TLS and stimulate T fh development (305, 306). T1-IFNs directly induce the expression of the T -markers CXCR5 and PD-1 on T cells (307, 308). Also, fh T1-IFNs promote the survival of aberrantly selected B-cells in the GC reactions during SLE directly and indirectly through BAFF induction as discussed in Section 4.2.2. Thus, it appears that by stimulating TLS development, the Th17 response facilitates FigURe 6 | Th17.1 responses in tuberculosis (TB). (1) Type I interferons an environment that promotes selection of autoreactive B-cells (T1-IFNs) induce CCL2 production in parenchymal cells and MDM, but not under influence of T1-IFNs and BAFF. + GMDM. This induces the influx of CCR2 monocytes that mediate Taken together, several lines of evidence exist for interac- detrimental effects in TB as Mtb-permissive cells develop upon T1-IFN stimulation. (2) GM-CSF increases IL-1β production, limits responsiveness to tions between the Th17 response and T1-IFNs in systemic AID. T1-IFNs, and increases Mtb-killing potential. However, the exact cellular Current data support a scenario in which Th17 immunity fuels source of GM-CSF in TB is unknown. (3) Patients with active TB overexpress T1-IFN-related pathology by mediating PMN influx and driving TGF-β, which may drive Th17 development over Th17.1 in the presence of TLS formation, which facilitates T1-IFN/BAFF-mediated plasma IL-1β and IL-23. Dotted lines implicate mechanisms shown in autoimmune cell responses and autoantibody production. In turn, T1-IFNs diseases that have not been confirmed in TB. Outstanding questions: (1) What is (are) the cellular source(s) of T1-IFNs in TB? (2) What is the ratio can support pathogenic Th17.1 responses in AID by driving the between different Th17 subsets in TB? (3) Do T-cells contribute to GM-CSF + + influx of CCR2 inflammatory monocytes and potentially CCR2 production in TB? Th17.1 cells themselves, which locally drive IL-1β mediated Frontiers in Immunology | www.frontiersin.org 17 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB that produce IL-17 upon transfer, predominantly produce IFN- However, elevated TGF-β levels in TB patients suggest a limited γ upon subsequent contact with Mtb, which is suggestive of a contribution of Th17.1 cells to disease, as TGF-β favors the devel- Th17.1 phenotype (210). opment of regular IL-17-producing Th17 cells. Regardless of its Th17.1 cells in AID result from prolonged innate IL-1β and cellular source, preclinical TB studies support a protective role IL-23 signaling. With regard to the role of IL-1β and IL-23 in for GM-CSF during acute infection. GM-CSF causes monocytes human TB, IL-1β is essential for the expansion of both IFN-γ IL- to differentiate into cells with decreased T1-IFN responsiveness + + + 17 Th17 cells and IFN-γ IL-17 Th17 cells (311, 312). IL-23 pro- and increased Mtb-killing potential compared to their M-CSF- + + motes the development of IFN-γ IL-17 Th17 cells but promotes differentiated counterparts. However, during chronic Mtb infec- − + IFN-γ IL-17 Th17 cells if TGF-β is concomitantly present (312). tion, high GM-CSF levels appear detrimental as they stimulate Since active TB is associated with elevated TGF-β levels (178, 313, foamy macrophage development and inflammation. 314), it is possible that Th17.1 cell differentiation does not play a major role, but this remains to be demonstrated. 5.2. The iL-17/T1-iFNs/BAFF Axis in TB Th17.1-derived GM-CSF exerts a pathogenic effect in AID by In the previous paragraph, it was discussed that regular IL-17- stimulating IL-1β production in CCR2 monocytes. Although producing T-cells are more likely to play a role in TB than Th17.1 the role of Th17.1 cells in TB is uncertain, other cells such cells. Opposed to Th17.1 cells, regular Th17 cells exert their effect as NK  cells and Th1  cells can also produce GM-CSF in TB, primarily through PMN instead of CCR2 monocytes in AID. and during the course of infection, GM-CSF levels progres- Particularly in SLE, this was shown to be part of a pathogenic axis sively increase in the lungs of Mtb-infected mice (125, 315). together with T1-IFNs and BAFF. The roles of T1-IFNs and IL-17 The functional role of GM-CSF is of interest in TB, because in TB have been discussed already in Sections 2 and 3. In this it importantly impacts on CCR2 monocytes, which play a section, we assess the roles of the other components of the IL-17/ central role in T1-IFN-mediated pathogenic effects. T1-IFNs T1-IFNs/BAFF axis in TB, which include PMN-derived NETs, stimulate the influx of inflammatory CCR2 monocytes but pDC, and BAFF (Figure 7). inhibit their IL-1β production and stimulate their differen- tiation into Mtb-permissive cells (see Figure  3). In contrast, GM-CSF is protective during acute TB, which is in line with the protective effects of IL-1β in this phase of disease. Mice deficient in GM-CSF succumb rapidly to infection due to their inability to mount Th1 responses (316, 317). Transgenic mice that overexpress GM-CSF in the lungs but are GM-CSF-deficient in all other organs can develop Th1 responses, but still succumb to infection more rapidly than wild-type mice due to their inability to develop a normal granulomatous response (316, 317). Evidence from in  vitro studies suggests that GM-CSF exerts its protective effect in TB by countering the effects of T1-IFNs in CCR2 monocytes (36, 94). Under physiological conditions, monocytes differentiate under influence of M-CSF into monocyte-derived macrophages (MDM). These MDM low have a CCR2 phenotype, readily produce CCL2 and IL-10 in response to T1-IFNs, and have a low Mtb-killing capacity (94, 156, 318, 319). Conversely, monocytes that differentiate high under influence of GM-CSF (GMDM) are CCR2 , relatively unresponsive to T1-IFN signaling, produce small amounts of CCL2 and IL-10, and have better Mtb-killing capacities than MDM in response to activation by IFN-γ (36, 126). e r Th elative unresponsiveness of GMDM to T1-IFNs might explain why preclinical studies primarily show effects of T1-IFNs during acute TB when the GM-CSF/M-CSF ratio in the lungs is relatively low, but less pronounced effects during later stages when GM-CSF-levels progressively increase (see Section 2.4.3; FigURe 7 | The iL-17/type i interferons (T1-iFNs)/B-cell activating factor (BAFF) axis in tuberculosis (TB). Mtb actively induces NET Figure 3) (125). However, similar to IL-1β, prolonged GM-CSF formation by PMN, but subsequent activation of IFN-α production by signaling also appears detrimental in TB. In particular, GM-CSF plasmacytoid dendritic (pDC) appears less relevant in TB than in autoimmune contributes to foamy macrophage development during later diseases (AID). IL-17 levels from TB patients vary (Table 3), but preclinical stages of infection, which can sustain persistent mycobacteria models support a protective role. Dotted lines implicate mechanisms present and contribute to inflammation (125, 320). in AID that have not been confirmed in TB. Outstanding questions: (1) What are the specific contributions of IFN-α vs. IFN-β to disease in the different In summary, relatively few data are available on Th17.1 cells or phases of TB? (2) Do BAFF and T1-IFNs promote the observed autoimmune T-cell-derived GM-CSF in TB. The requirement for antigen stim- phenomena in TB? ulation of T-cells to induce expression of GM-CSF is interesting. Frontiers in Immunology | www.frontiersin.org 18 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB 5.2.1. PMN, NETs, and pDC in TB BOx 4 | iFN-α or iFN-β: which is relevant in tuberculosis (TB)? PMN isolated from SLE patients are the primary cells that IFN-α and IFN-β both exert their effect by binding to IFN-α/β receptor, but express the transcriptional T1-IFN signature. Furthermore, a increasing evidence from autoimmune diseases (AID) and viral infections sug- specific subclass of PMN, termed low-density granulocytes gests divergent effector functions (328, 329). In AID, this is illustrated by the (LDG) have been identified in SLE that express a pro- pathogenicity of IFN-α in systemic lupus erythematosus (SLE) opposed to the inflammatory phenotype, has increased T1-IFN-production therapeutic application of IFN-β as immunosuppressive treatment in multiple sclerosis (MS). Recently, these different immunoregulatory roles of IFN-α and and more readily form NETs than PMN from healthy indi- IFN-β in SLE and MS have been confirmed by more detailed analysis of blood viduals (291, 292). Similar to SLE, the transcriptional T1-IFN transcriptional profiles in patients (330). The molecular explanation for the signature in TB patients is mostly expressed in PMN (58). differential function of IFN-α and IFN-β traces back to subtle differences in Moreover, LDG are also present in TB patients and correlate receptor binding, signaling cascades, and feedback mechanisms initiated and with disease severity, but it is unclear if these cells also have a has been reviewed in detail elsewhere (28, 331). The specific contributions of IFN-α and IFN-β to the host response in infec- similarly increased tendency for NETosis as their SLE counter- tious disease have been studied particularly in mice infected with lymphocytic parts (321). Nevertheless, NETosis does occurs in TB, as Mtb choriomeningitis virus. This work supports an immune-stimulating, antiviral readily induces NETosis itself in PMN in an ESX-1-dependent role for IFN-α as opposed to an immunosuppressive effect by IFN-β (328, 331, way and can even stimulate extracellular trap formation in 332). IFN-β specifically inhibits antiviral T-cell responses and promotes viral persistence (331). In contrast, IFN-α-signaling associates with tissue damage macrophages (204, 322–324). and antiviral activity (331, 332). Neutrophil extracellular traps are strong inducers of IFN-α In TB, evidence for the involvement of both type I interferons is present. production in pDC in SLE (256). Conversely, pDC produce only Reactivation of TB has been reported specifically after treatment of patients small amounts of IFN-α and appear of minor clinical significance with IFN-α, but not IFN-β (50–57). Also, mice infected with virulent Mtb strains in TB (325). In accord, circulating pDC are elevated in SLE (326) specifically show higher IFN-α levels in the lungs compared to less virulent strains (64, 65). However, IFN-α-producing plasmacytoid dendritic cells seem but reduced in TB patients (327). to be of minor significance in TB patients (325, 327), and preclinical studies Final support for a limited role of pDC in TB pathogenesis show that Mtb preferentially induces IFN-β through cytoplasmic pattern comes from the observation that pDC produce IFN-α aer en ft do- recognition receptors and IRF3 instead of IFN-α through endosomal toll-like somal TLR-activation, while it is shown that Mtb primarily induces receptors and IRF7 (79–81). Mycobacterial persistence in patients with TB IFN-β through activation of cytoplasmic PRRs (see Section 2.3) is a major clinical problem and in line with the immunosuppressed state in active TB primarily supports a role for IFN-β (178, 333). However, exaggerated (81, 250). While both IFN-α and IFN-β signal through IFNAR, innate responses are also observed in TB where IFN-α might be involved. this diversification in cellular source and type of T1-IFN that is This is supported by recent evidence showing that IRF7 drives excessive induced can have important consequences for TB pathogenesis innate inflammation during bacterial infections and provides an interesting (see Box 4). therapeutic target (334). Taken together, little is known about the separate effects of IFN-α and IFN-β in TB, but clinical and preclinical studies support a role for both in different disease contexts. The diversification of IFN-α and 5.2.2. BAFF in TB IFN-β responses in transcriptional signatures observed in AID patients and the Both T1-IFNs and IL-17 can induce BAFF expression, which con- distinct effects of IFN-α and IFN-β in experimental LMCV infection therefore tributes to disease in SLE as illustrated by the clinical successes of provide highly interesting perspectives for TB. BAFF-inhibition (261, 271, 335). BAFF increases B-cell numbers and antibody titers (293, 336) and treatment with anti-BAFF in Additional support for a supposed protective role of BAFF in SLE patients reduces serum IgG levels (335). The role of BAFF in TB comes from its interaction with IL-17, which shows protective TB has been explored to a much lesser extent, with currently one effects in preclinical early infection phase TB models, as discussed paper demonstrating BAFF levels to be elevated in patients with active TB without elaborating on its functional contribution to in Section 3. IL-17 stimulates the migration of PMN to lymphoid structures where they can produce large quantities of BAFF that the host response (337). The functional role of BAFF in TB might be of particular directly drive plasma cell responses. Also, IL-17-induced G-CSF primes PMN for BAFF production upon activation (271, 294). interest given its stimulation of humoral immunity and the recently demonstrated protective effects of antibody-mediated Vice versa, elevated BAFF levels have been reported to increase Th17 immunity in AID and infection (268, 269, 343). immunity in TB patients (338, 339). Next to antibody-mediated protection, B-cells also essentially support T-cell responses in Taken together, preliminary pieces of evidence support the presence of interactions between IL-17, T1-IFNs, and BAFF in TB, but circulating B-cells are dysfunctional and reduced in absolute numbers in patients with active TB (340). The protec- TB, similar to those demonstrated in AID. This primarily includes the presence of NETs and elevated BAFF levels. However, despite tive effects of Mtb-specific antibodies and B cells in TB suggest that increased BAFF levels may supports host responses by the T1-IFN signature observed in TB, NET-induced IFN-α production by pDC appears less relevant in TB than in AID, and stimulating antibody production and perhaps other B cell func- tions such as stimulating T cell responses (338). However, high the specific contributions of IFN-α and IFN-β are of high inter - est in TB, but currently largely unknown. Studies in TB patients BAFF levels also predispose for the development of autoreactive B-cells in AID (341). Thus, elevated BAFF levels in TB could show protective effects of antibody-mediated immunity but also elevated titers of autoantibodies. This supports a view in which relate to the observation that up to 32% of patients with active TB have elevated autoantibody levels (12). Such correlations BAFF is protective in TB, but excessive BAFF levels, driven by either T1-IFNs or IL-17 can also increase the chances of develop- between elevated BAFF levels and autoimmunity have been demonstrated in other chronic infections (342). ing autoimmunity in TB patients. Frontiers in Immunology | www.frontiersin.org 19 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB Another interesting observation regarding T responses fh 5.3. TLS in TB concerns the induction of PD-L1 expression on APC and PD1 As a third place of interaction, IL-17, T1-IFNs, and BAFF converge on T-cells by T1-IFNs (43, 136, 307). In TB circulating PMN pri- in the local formation and functioning of TLS. In these structures, marily express the T1-IFN signature but also overexpress PD-L1 T cells support GC reactions in which B-cells differentiate into fh (58, 347). e in Th teraction of PD-L1 with PD1 on CD4 T-cells plasma cells and memory cells (295). As discussed in Section 4.3.4, is a key immunological checkpoint in TB that limits excessive observations in AID suggest that Th17 responses drive TLS devel- T-helper responses (33, 35). In line with this, PD1-deficient mice opment and facilitate an environment that promotes development are extraordinarily susceptible to TB (34). T cells constitutively fh of autoreactive B-cells under influence of T1-IFNs and BAFF. + + express PD1 , which distinguishes them from conventional CD4 Conversely, both TLS and Tfh cells are associated with immune T cells. Interestingly, while increased PD1/PD-L1 interaction control in TB patients and preclinical TB models, which is in line suppresses conventional T-helper responses, the opposite is with the protective role of humoral immunity in TB discussed in observed for T responses (348). Interaction between PD1 T fh fh the previous section (194, 201, 344, 345). Here, we discuss how cells with PD-L1 has a stronger suppressive effect on the regula- TLS and Tfh responses are associated with protective immunity in tory subset of T cells than on stimulatory T cells and results in fh fh TB and how interactions between IL-17, T1-IFNs, and BAFF may a net increase of T activity (348). fh contribute to this immune response. Taken together, IL-17, T1-IFNs, and BAFF act in concert to Migration of CXCR5 T cells into TLS is largely dependent on fh drive TLS formation and T responses. es Th e responses support fh CXCL13, which is primarily induced by IL-23 and IL-17 in mouse the development of autoreactive B-cells and the subsequent pro- TB models but can also be induced by T1-IFNs, as demonstrated duction of autoantibodies in AID but confer protective immunity in viral infections (194, 346). Mechanistically, CXCR5 Tfh cells in TB by improving the interaction between adaptive and innate mediate their protective effect in Mtb-infected mice by facilitat- cells and facilitating antibody production, while simultaneously ing optimal localization of effector T-cell populations within the inhibiting excessive inflammation by conventional CD4 T-cell lung parenchyma, thereby promoting efficient T-cell-dependent responses. macrophage activation and intracellular Mtb killing (194, 201). 6. CONCLUDiNg ReMARKS The notion that complex mechanisms beyond Th1 immunity are at play in TB immunity is supported by (1) the unsatis- factory results of vaccine strategies aimed at boosting Th1 immunity in TB patients (31); (2) the inflammatory damage associated with increasing IFN-γ production by T-cells in the lungs of Mtb-infected mice (33); and (3) the host-detrimental effect of targeting the Th1-inhibiting PD1/PD-L1 interaction in mice (34, 35). Patients with active TB express a T1-IFN transcriptional signature in their circulating leukocytes, but the exact identity and functional role of T1-IFNs in patients remains to be elu- cidated (62). Others have speculated that deleterious effects of T1-IFN-signaling during bacterial infections are tolerated because of their ability to suppress myeloid cell responses (41). This review highlights two additional aspects of T1-IFNs that are of interest in TB. The first concerns the preconditioning of myeloid cells prior to their contact with T1-IFNs. IFN-γ prim- ing appears essential for the induction of an Mtb-permissive phenotype, and monocytes that differentiate under GM-CSF are less responsive to T1-IFNs than their M-CSF-differentiated counterparts (Figure 3) (43, 94). The second aspect is the diver - sification of IFN-α and IFN-β responses on a transcriptional and functional level as explained in Box 4. We propose that the FigURe 8 | Tertiary lymphoid structures (TLS) in tuberculosis (TB). TLS, Tfh cells, B-cells, and antibodies are all associated with protective inflammatory effects of IRF7-mediated IFN-α might contribute immunity in TB. Preclinical TB models show that TLS induction and CXCL13 to excessive innate inflammatory responses in TB, while the production are driven by IL-17 and IL-23. Type I interferons (T1-IFNs) and immunosuppressive effects of IFN-β are more likely to support B-cell activating factor (BAFF) support TLS function and Tfh responses in mycobacterial persistence. autoimmune diseases (AID). In TB, T1-IFNs and BAFF are associated with active disease, but their functional role remains to be identified. Dotted lines Determination of the role of the Th17 response in TB is implicate mechanisms present in AID that have not been confirmed in TB. impeded by its heterogeneity, reflected in the presence of Outstanding question: (1) What are the functional roles of T1-IFNs and BAFF different Th17 subsets with ranging inflammatory potentials. in TLS function and humoral immunity in Mtb infection? Observations in AID emphasize the difference between IFN-γ/ Frontiers in Immunology | www.frontiersin.org 20 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB GM-CSF-producing Th17.1 cells and regular IL-17-producing this manuscript for intellectual content, approved its final ver - Th17  cells. The exact role of T-cell-derived GM-CSF in TB sion for publication, and have agreed to be accountable for all remains to be determined, but preclinical TB studies show a pro- aspects of the work and in ensuring that questions related to the tective role for GM-CSF on monocyte differentiation in the acute accuracy or integrity of any part of the work are appropriately phase of TB. In contrast, IL-17 and PMN appear more relevant in investigated and resolved. chronic control of Mtb infection and recall immunity. Immunological similarities between TB and AID may result ACKNOwLeDgMeNTS from commonly activated pathogenic pathways. Alternatively, compensatory mechanisms induced by one disease might pre- e a Th uthors thank Ko Hagoort for his critical reading of the manuscript and Servier Medical Art (http://servier.com/ dispose for the development of the other. Interactions between IL-17, T1-IFNs, and BAFF form a pathological axis in AID that Powerpoint-image-bank) for providing base images for the figures. EL acknowledges the Dutch Arthritis Association promote autoantibody-mediated autoimmunity. e n Th ewly appreciated functional roles of antibodies, B-cells, (12-02-409; 13-3-403; 14-02-201; and 15-2-206). TO acknowl- cells in TB provide suggestive evidence that pathogenic edges EC FP7 ADITEC (Grant Agreement No. 280873); EC and Tfh mechanisms in AID confer protective immunity to TB. Further, HORIZON2020 TBVAC2020 (Grant Agreement No. 643381); insight into these mechanisms as discussed in Figures 6–8 may EC FP7 EURIPRED (FP7-INFRA-2012 Grant Agreement No. generate leads for immune-directed therapies adjunct to current 312661); The Netherlands Organization for Scientific Research and newly developed antimicrobial treatment protocols. (NWO-TOP Grant Agreement No. 91214038); The Bill & Melinda Gates Foundation Grand Challenges in Global Health (Grant GC6-2013); and the National Institute of Allergy and AUTHOR CONTRiBUTiONS Infectious Diseases of the National Institutes of Health under BM has written the manuscript and drafted the figures; EL Award Number R21AI127133. Research for this manuscript was has written the initial version of Section 4 and contributed (in part) performed within the framework of the Erasmus post- to the conception of Figure  5; JS and TO have contributed graduate school Molecular Medicine. The content is solely the substantially to Sections 1, 2, 3, and 5 and the conception of responsibility of the authors and does not necessarily represent Figures 1–3; PL has contributed substantially to the design of the official views of any funder. 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Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

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1664-3224
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10.3389/fimmu.2017.00294
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Abstract

Review published: 05 April 2017 doi: 10.3389/fimmu.2017.00294 interactions between Type 1 interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases 1 2 1 3 Bas C. Mourik , Erik Lubberts , Jurriaan E. M. de Steenwinkel , Tom H. M. Ottenhoff and Pieter J. M. Leenen * Department of Medical Microbiology and Infectious Diseases, Erasmus University Medical Center, Rotterdam, Netherlands, 2 3 Department of Rheumatology, Erasmus University Medical Center, Rotterdam, Netherlands, Department of Infectious Diseases, Leiden University Medical Center, Leiden, Netherlands, Department of Immunology, Erasmus University Medical Center, Rotterdam, Netherlands The classical paradigm of tuberculosis (TB) immunity, with a central protective role for Th1 responses and IFN-γ-stimulated cellular responses, has been challenged by unsatisfactory results of vaccine strategies aimed at enhancing Th1 immunity. Moreover, preclinical TB models have shown that increasing IFN-γ responses in the lungs is more damaging to the host than to the pathogen. Type 1 interferon signaling and altered Th17 Edited by: responses have also been associated with active TB, but their functional roles in TB Laurel L. Lenz, pathogenesis remain to be established. These two host responses have been studied University of Colorado Denver School of Medicine, USA in more detail in autoimmune diseases (AID) and show functional interactions that are Reviewed by: of potential interest in TB immunity. In this review, we first identify the role of type 1 Roland Lang, interferons and Th17 immunity in TB, followed by an overview of interactions between University Hospital Erlangen, Germany these responses observed in systemic AID. We discuss (i) the effects of GM-CSF- Rolf Billeskov, secreting Th17.1 cells and type 1 interferons on CCR2 monocytes; (ii) convergence of Statens Serum Institut, Denmark IL-17 and type 1 interferon signaling on stimulating B-cell activating factor production *Correspondence: and the central role of neutrophils in this process; and (iii) synergy between IL-17 and Pieter J. M. Leenen [email protected] type 1 interferons in the generation and function of tertiary lymphoid structures and the associated follicular helper T-cell responses. Evaluation of these autoimmune-related Specialty section: pathways in TB pathogenesis provides a new perspective on recent developments in This article was submitted to Microbial Immunology, TB research. a section of the journal Keywords: Mycobacterium tuberculosis, autoimmune diseases, neutrophils, inflammation, tertiary lymphoid Frontiers in Immunology structures, antibodies, B-cell-activating factor Received: 21 December 2016 Accepted: 01 March 2017 Published: 05 April 2017 1. iNTRODUCTiON Citation: Tuberculosis (TB) has been responsible for an estimated one billion deaths worldwide over the last Mourik BC, Lubberts E, de Steenwinkel JEM, Ottenhoff THM 200 years (1), which is more than any other infectious disease caused by a single pathogen. Given its and Leenen PJM (2017) Interactions global magnitude, it has been hypothesized that TB particularly contributed to the genetic selective between Type 1 Interferons pressure that predisposes for development of autoimmune diseases (AID) (2). This is supported by and the Th17 Response in polymorphism studies of the TNF gene, which show an opposite association between susceptibility Tuberculosis: Lessons Learned to TB vs. susceptibility to several AID (3). Additionally, a gender-dependent predisposition to either from Autoimmune Diseases. TB or AID exists with a male predominance among TB patients (4) opposed to increased AID Front. Immunol. 8:294. doi: 10.3389/fimmu.2017.00294 incidences in women (5). The general concept of an inverse relation between infectious diseases and Frontiers in Immunology | www.frontiersin.org 1 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB AID is best described by the hygiene hypothesis, which states that by activating dendritic cells and NK cells and by stimulating both + + diminished exposure to infectious pathogens during childhood /CD8 T-cell responses. However, B-cell responses and CD4 increases the chances of developing AID and allergies (6, 7). Also, T1-IFNs can also induce anti-inflammatory responses to control epidemiologically, the decline in burden of infectious diseases immune-mediated tissue damage during chronic infections. over the last century in industrialized countries is accompanied es Th e contradictory effects of T1-IFNs in different situations by increasing rates of AID (8). can likely be ascribed to the heterogeneity of the T1-IFNs family, Despite support for an inverse relation, similarities between downstream activation of different STAT homo/heterodimers aer b ft inding to IFNAR (38, 42) and to differential priming of TB and AID have also been identified. TB is even hypothesized to be an infection-induced AID based on the observation that cells prior to induction of T1-IFN signaling (43). diverse clinical autoimmune phenomena frequently occur in TB patients (9, 10). Furthermore, up to 32% of patients with active 2.1. T1-iFNs in Human TB TB have elevated autoantibody titers (11, 12). Rational explana- When recombinant or purified T1-IFNs became available as tions for these findings could be that either TB or AID activate therapeutic agents in the 1980s, different applications have been common immunological pathways (10), or protective immunity established based on their antiviral, immune-stimulating, and in TB increases the chance to develop AID (2). In both scenarios, suppressive effects. These include treatment of viral infections key findings in AID immunology could potentially contribute to (e.g., IFN-α treatment of hepatitis B/C infections), AID [e.g., our understanding of TB pathogenesis. IFN-β treatment for multiple sclerosis (MS)], and various malig- The current paradigm of the host response to Mtb infection nancies (44). Based on their well-described immune-stimulating is summarized in Figure  1. The indispensable role of IL-12/ effect, the use of T1-IFNs as adjuvant to antibiotic treatment for IFN-γ-mediated Th1 immunity against Mtb has long been patients with active TB has also been explored (see Table 1). All recognized (13). However, stimulating Th1 immunity in TB studies found a positive influence of adjuvant T1-IFN therapy can also result in excessive inflammation (see Box  1 ). More on clinical outcomes in active TB (45–49). Conversely, IFN-α recently, the contributions of additional immune pathways treatment without concomitant antibiotic treatment, e.g., for have been explored, especially the role of type I interferons hepatitis C, has been described to cause reactivation of latent TB (T1-IFNs), Th17 immunity (14, 15), and unconventional (50–57). While reactivation of latent TB and treatment of active T  cell immunity (16–18). Little is known about the potential TB are two distinct clinical situations, the latter finding suggests interaction between T1-IFNs and Th17 responses in TB, but an unfavorable role for T1-IFNs in TB pathogenesis. interesting observations in this regard have been reported for In 2010, an interferon-inducible transcriptional signature was multiple AID (19–21). To determine if these findings are rel- reported in circulating leukocytes of TB patients, thus linking evant for the understanding of TB pathogenesis, we first review increased T1-IFN signaling with active disease (58). This find- the separate involvements of T1-IFNs and Th17 responses ing has been validated in several independent studies (59–62). in TB pathogenesis in Sections 2 and 3, respectively. Next, A meta-analysis confirmed statistical significance but found a their known interactions in AID are discussed in Section  4. less dominant role for T1-IFN-related genes than expected (63). Finally, in Section 5, the potential relevance of these interacting This is ascribed to the involvement of signaling components pathways in TB is assessed and integrated into the current downstream of the T1-IFNs receptor in multiple overlapping understanding of TB pathogenesis. intracellular pathways. Also, association studies do not neces- sarily implicate a causally detrimental effect of T1-IFNs in TB 2. T1-iFNs iN TB pathogenesis. In line with this, T1-IFN responses show potential as biomarkers or diagnostic tool for risk of active disease, but Type I interferons comprise a family of 13 IFN-α subtypes, IFN-β, their functional involvement during TB progression in patients IFN-ε, IFN-κ, and IFN-ω, which have the shared ability to bind to is not yet understood (62). the IFN-α/β receptor (IFNAR) (37). Other interferons include the single type II interferon, interferon-γ, and the type III interferon 2.2. Preclinical Studies in Mice Support a family covering three IFN-λ types. Detrimental Role of T1-iFNs during All nucleated cell types are capable of both producing T1-IFNs and responding to them, while type II/III interferons are mostly Acute TB produced by leukocytes (37). The main function of T1-IFNs is A causal relationship between T1-IFN signaling and TB disease severity was first suggested in 2001 when IFN-α levels in the to “interfere” with intracellular infections. Therefore, T1-IFN expression is primarily induced through cytoplasmic pattern lungs of Mtb-infected mice were shown to be associated with Mtb strain virulence (64). Several approaches have been used recognition receptors (PRRs) and endosomal toll-like receptors (TLRs), which activate distinct interferon regulatory factors to verify this relationship between increased T1-IFN signaling and unfavorable disease outcome. Blocking the T1-IFN signaling (IRFs) that act as transcription factors enabling expression of −/− interferon-responsive genes (38). In contrast, extracellular patho- pathway through use of IFN-α/β receptor knockout (IFNAR ) improves survival, but only when applied on the background of gens trigger surface-bound TLRs that preferentially induce IL-1β and TNF-α through activation of NF-κB. mouse strains in which acute TB is lethal, such as the A129 strain −/− (65). In IFNAR mice with a relatively TB-resistant C57BL/6 e Th role of T1-IFNs in infectious diseases is complex (15, 39– 41). T1-IFNs boost the immune system upon pathogen encounter background, survival rates were similar to wild-type mice, but Frontiers in Immunology | www.frontiersin.org 2 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB FigURe 1 | The phases and cell types involved in the immune response to tuberculosis (TB) in the lungs. (1) Inhaled Mtb-containing aerosols are deposited deep into the lung, reaching the alveoli (22). Within the alveoli, Mtb are phagocytosed by alveolar macrophages (Alv. MΦ) or infect alveolar epithelial cells prior to ending up in alveolar macrophages (23). Within Alv. MΦ, the bacteria are able to inhibit phagosome–lysosome fusion and replicate until cell lysis ensues, which takes approximately 3–5 days (24). (2) After the initial contact, Mtb encounters infiltrating myeloid cells of which inflammatory dendritic cells and PMN are most readily infected (13, 25). During these early phases, invariate natural killer (iNK) cells and type 1 innate lymphoid cells (ILC1) produce IFN-γ in response to IL-12 and stimulate myeloid cells to kill phagocytosed Mtb. In addition, γδ T-cells and ILC3 produce IL-17. There is increasing appreciation for the role of tertiary lymphoid structures (TLS) and their associated germinal centers (GC) that arise under influence of IL-17 and facilitate optimal activation of myeloid cells and efficient recall responses. During this process, loosely aggregated “innate granulomas” are already formed (26). It should be noted that the roles of ILC1s and ILC3s are based on their general function, which has not yet been formally demonstrated in TB (27). (3) Onset of adaptive immunity in Mtb infection is delayed to circa 14 days in mice and up to 6 weeks in humans (13, 22). At this point, distinct T-cell subsets and B-cells migrate to the site of infection and execute their different effector functions. (4) After onset of adaptive immunity, 90–97% of infected individuals develop sustained infection without clinical symptoms termed “latent TB infection” (LTBI) (13). LTBI was initially considered a static phase, but it is now known that this stage is hallmarked by the presence of granulomas in various stages (caseous, non- caseous, and fibrotic) and an ongoing balance between antimycobacterial activity and regulatory mechanisms to minimize immunopathology (13, 28). Cell phenotypes are as present in mouse TB models. Frontiers in Immunology | www.frontiersin.org 3 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB (67, 77–81). ESAT-6 can disrupt the phagosomal membrane, BOx 1 | The dual faces of iFN-γ in tuberculosis (TB) immunity. which allows translocation of mycobacteria and mycobacterial In the current paradigm of a successful host response, lung DCs migrate to the products from the phagosome into the cytosol (78, 82). draining lymph node after Mtb contact and induce a robust IL-12-mediated Mycobacteria actively secrete several T1-IFN-inducing com- Th1 response (13). This results in migration of IFN-γ-producing CD4 T-cells to pounds, including double-stranded (ds)DNA and the bacterial the site of infection. Subsequently, activation of macrophages by IFN-γ results in killing of intracellular Mtb, while activated CD8 T-cells lyse infected host second messenger cyclic-di-AMP (83). These compounds are cells. Conversely, unsuccessful clearance of infection is due to poor activation recognized by different cytosolic PRRs, including cGAS (80), of adaptive immunity. This can result from insufficient antigen presentation IFI-204 (78), AIM2 (84), and possibly NOD2 (77), although data (29), or from the action of regulatory factors that interfere with Th1 responses on the latter are conflicting (67, 78). Activation of these cytosolic such as IL-10 or PDL1-PD1 interaction (13). Paradoxically, the current vaccine PRRs converges to activate “STimulator of INterferon Genes” bacillus Calmette–Guérin (BCG) induces a strong Th1 response but is only partially effective in protecting against TB (30). Boosting the Th1-inducing (STING), which subsequently forms a complex with TANK- potential of BCG by using a modified Ankara virus also has yielded disap- binding kinase 1 (79). This STING–TBK1 complex activates pointing results (31, 32). Thus, solely stimulating Th1 immunity might not be IRF3, leading to IFN-β production in mice (81) as well as human the solution in TB prevention. This is confirmed in a mouse TB study showing −/− mice are poor producers of IFN-β and dendritic cells (74). IRF3 that increasing IFN-γ production by T-cells in the lungs is detrimental to the more resistant to Mtb infection, which supports a negative role host due to hyper-inflammation that requires PD-1-mediated suppression to limit pathology (33). In line with this, Mtb-infected mice deficient in PD-1, or for T1-IFNs in TB pathogenesis (78). −/− mice in which PD-1 is selectively inhibited, display excessive inflammation However, the overall picture is more complex. IRF3 mice are and disease progression (34, 35). Finally, ex vivo studies in human monocyte- more resistant to Mtb infection, but mice deficient in the cytosolic derived macrophages show that protective effects of IFN-γ are dependent on PRR cGAS, upstream of IRF3, show diminished control of chronic multiple factors including time of contact, concentration, and the magnitude of Mtb infection (79). This can be traced back to a concomitant the ensuing microbial challenge (36). Based on these observations, it can be concluded that boosting IFN-γ production and Th1 immunity in TB, besides reduction in autophagy, which is also dependent on the cGAS- potentially enhancing protection, can also result in unbalanced inflammation induced activation of the STING–TBK1 axis, but independent in the lungs that is more harmful to the host than to the pathogen. This of IRF3. In line with this, mice infected with an Mtb strain that emphasizes the need for involvement of additional immunological pathways induces higher amounts of cyclic-di-AMP, thus stimulating both for optimal protection. IRF3-mediated IFN-β production and STING–TBK1-mediated autophagy, show improved survival despite increased IFN-β levels (83). Taken together, this suggests that pro-mycobacterial mycobacterial loads in the lungs were lower (66–69). One study effects of stimulating the cytosolic PRR/STING/IRF3/IFN-β axis actually observed increased loads in the lungs (70) (Table 2). by mycobacteria might be outweighed by the antimycobacterial In a second approach, Mtb-infected mice were supplemented effects of the PRR/STING/autophagy pathway. with T1-IFNs aer ft start of infection or treated with the TLR3- Autocrine or paracrine IFN-β-signaling induces IRF7 and ligand poly-ICLC, which stimulates T1-IFN production and leads to the production of IFN-α in human dendritic cells signaling (64, 72). Both studies showed increased mortality and (74). In line with this, injection of recombinant IFN-β in mice higher mycobacterial loads in the supplemented groups, which induces IFN-α production (85). Alternatively, myeloid cells and were not observed when T1-IFNs or poly-ICLC were adminis- particularly plasmacytoid dendritic (pDC) cells are capable of −/− tered to Mtb-infected IFNAR mice. Finally, in a third approach, directly activating IRF7-mediated IFN-α production aer r ft ecog- mice were primed with a T1-IFN-inducing influenza virus prior nition of Mtb, particularly by endosomal TLR9 (86). In TB, this to TB infection, which led to enhanced mycobacterial growth and TLR9-IRF7 pathway is studied to lesser extent than the cytosolic reduced survival (73). PRR–IRF3 axis (87). This is possibly due to the dependence of −/− Enigmatically, reduced mycobacterial loads in IFNAR mice T1-IFN-mediated pathogenic effects in mice on ESX-1, which are primarily observed in the acute phase of infection in which induces IRF3 rather than IRF7 as explained above (67). However, T1-IFNs are considered immune stimulating. No differences in IRF7 is recognized as commonly induced transcription factor survival or long-term control of infection were found in C57BL/6 by multiple clinical Mtb strains in alveolar epithelial cells (88). −/− IFNAR mice compared to wild type. In support of this notion, −/− mice succumb earlier to high-dose Mtb infec- Moreover, TLR9 T-cell analyses in several of the abovementioned studies con- tion than wild-type mice, which suggests a role for the TLR9/ vincingly excluded an effect of increased or decreased T1-IFN IRF7/IFN-α axis in TB as well (89). signaling on the adaptive immune response (68, 69, 72). Notably, none of these studies addressed the effect of T1-IFNs as adjunct treatment to antibiotics, which was shown to be beneficial in TB 2.4. T1-iFNs Drive the influx of patients (Table 1). Mtb-Permissive Myeloid Cells during Acute infection 2.3. Mtb Actively induces T1-iFNs Most studies in mouse TB models found significant functional + int effects of T1-IFNs specifically on CD11b Gr1 myeloid cell Multiple studies indicate that Mtb employs both active and pas- sive mechanisms to induce T1-IFNs (74–76). The mycobacterial populations (68, 69, 72). This population comprises monocyte- high − high derived Ly6C CD11c CCR2 inflammatory macrophages ESAT-6 secretion system (ESX-1) and its 6  kDa early secre- int + int tory antigenic target (ESAT-6) are essential in this process, as (iM) and Ly6C CD11c CCR2 inflammatory dendritic cells + high (iDC), but not CD11b Gr1 PMN (90). This is an important mycobacteria lacking ESX-1 fail to induce T1-IFN production Frontiers in Immunology | www.frontiersin.org 4 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB Frontiers in Immunology | www.frontiersin.org 5 April 2017 | Volume 8 | Article 294 TABLe 1 | effect of type i interferons supplementation in human tuberculosis (TB). Study design Regimen Outcome Side effects Reference Open parallel, susceptible Mtb No adverse Giosue et al. HRZE vs. HRZE + IFN-α – Less fever on days 3 and 4 after start treatment in HRZE + IFN-α group strain, HIV (−), N = 20 (2 × 10), – Increases in total lymphocytes and HLA DR1 cells after 2 months only in HRZE + IFN-α group effects reported (45) 2 months treated – Reduction in HRCT score only in HRZE + IFN-α group – Stronger reduction of pro-inflammatory cytokines in BALF after 2 months treatment in HRZE + IFN-α group Patients treated prior for 3–12 years, Anti-TB treatment + IFN-α – 2/5 complete response Flu-like symptoms Palmero et al. MDR strain, HIV (+), N = 5, – 1/5 partial response in 4/5 patients, (46) 12 weeks treated – 2/5 no response not needing – Increase of NK (% cytotoxicity) in all patients after 12 weeks treatment Patients treated prior for 6 months, DOT + IFN-α – Significant drop (p = 0.02) in Mtb loads at the end of a 9-week IFN-α treatment course No adverse Giosue et al. MDR strain, HIV (−), N = 7, 9 weeks – Significant increase (p = 0.03) in Mtb loads after stop of IFN-α treatment effects reported (47) treated – Significant drop in IL-1β, IL-6, TNF-α, and IFN-γ pro-inflammatory cytokines; IL-4 and IL-10 showed inconsistent changes Parallel, patients treated prior for 1. DOT – After 8 weeks, all five subjects of the case group became sputum smear negative; the control group 4 subjects mild Mansoori et al. 6 months with DOT, MDR strain, HIV 2. DOT + IFN-α remained smear positive (p = 0.012) arthralgia and (48) (−), N = 12 (2 × 6), 8 weeks treated – Evaluation of smear results after 6 months showed two smear-negative subjects in the case group while all myalgia, flu-like controls were smear positive (p = 0.132) symptoms in all subjects Case report, MDR strain, HIV (−), HRZE + IFN-α – Two months after initiation of therapy, sputum smears became negative, the patient’s clinical and No adverse Zarogoulidis N = 1, 2 months treated radiological findings strikingly improved. During 4-year follow-up, all consecutive sputum cultures remained effects reported et al. (49) negative Green text indicates a host-beneficial effect in TB; BALF, bronchoalveolar lavage fluid; DOT, directly observed therapy (antibiotic TB treatment); HRCT, high-resolution computed tomography; HRZE, isoniazid, rifampicin, pyrazinamide, and ethambutol; MDR, multidrug resistant. Mourik et al. Interactions between T1-IFNs and Th17 in TB TABLe 2 | interference with T1-iFN signaling in preclinical tuberculosis (TB) studies. Mouse intervention Mtb strain Survival Mtb load Reference back ground A129 IFN-α/β receptor HN878, W4, CDC1551, Better survival against CDC1551 No data Manca et al. (65) knockout 100–200 CFU, aerosol Trend toward better survival −/− (IFNAR ) against HN878 B6D2/F1 Anti-IFN-α/β HN878, 100–200 CFU, aerosol Better survival against HN878 No differences up to day 100 Manca et al. (65) antibody −/− B6/129 IFNAR H37Rv, HN878, CSU 93, CSU No differences in survival after Lower Mtb loads in lungs after infection Ordway et al. (66) 123 50–100 CFU, aerosol infection with all strains with all strains up to day 150 −/− 6 B6 IFNAR Erdman, 10  CFU, i.v. injection No data No differences in lung until day 20 Stanley et al. (67) Lower Mtb loads in spleen at day 10 and day 20 −/− B6 IFNAR H37Rv, 100 CFU, aerosol No differences up to day 70 Lower Mtb loads in lungs at day 18, Desvignes et al. (68) no differences at day 25 −/− 129S2 IFNAR H37Rv, 200 CFU, aerosol Improved survival Lower Mtb loads at day 21 Dorhoi et al. (69) −/− B6 IFNAR H37Rv, 500 CFU, aerosol No differences in survival up to Lower Mtb loads at day 21 Dorhoi et al. (69) day 90 −/− B6.SJL IFNAR H37Rv, 100–150 CFU, aerosol No differences in survival up to No data Mayer-Barber et al. (71) day 90 −/− B6/129 IFNAR Erdman, 100 CFU, aerosol No data Higher Mtb loads in lungs on day 10, Cooper et al. (70) day 20, and day 40 Equal loads at day 80 Green text indicates a host-beneficial effect in TB, while red indicates harmful effects. i.v., intravenous; CFU, Colony Forming Units. distinction, as T1-IFNs actively inhibit PMN influx, as discussed main source of this chemokine (94–96). Expression of CCL2 is −/− in more detail in Section 2.4.3. reduced in the lungs of IFNAR mice, and the pathogenic effects −/− Inflammatory macrophages and iDC have been identified as of poly-ICLC treatment are absent in Mtb-infected CCR2 mice major contributors to disease progression in mouse TB models (72). Thus, preclinical TB studies indicate that T1-IFNs stimulate (91–93). Several lines of evidence suggest that T1-IFNs regulate the influx of CCR2 monocytes, but not PMN, to the site of the influx of these cells and play a role in their functional impair - infection in a CCR2-dependent way via the induction of CCL2 ment to resist Mtb. This interference with protective immunity in parenchymal cells (74–76). is multifaceted and concerns four important interactions, which 2.4.2. T1-IFNs Inhibit IL-1β Responses will be reviewed separately: (1) T1-IFNs mediate the influx of iM and iDC. (2) T1-IFNs inhibit IL-1β responses by these cells, which during Acute TB are essential in the initial host responses to Mtb. (3) Prolonged Type I interferons not only stimulate the influx of CCR2 mono- IL-1β signaling can also cause excessive inflammation and thus cytes but also stimulates their differentiation into Mtb-permissive requires regulation during later phases. This can be mediated by iM and iDC (72, 75, 76). This can be traced back to a cross talk T1-IFNs but also by IFN-γ through functionally different routes. between T1-IFNs and IL-1β (71, 90). iM and iDC are the major (4) T1-IFNs and IFN-γ show a complex interplay in the activation sources of IL-1β in the lungs Mtb-infected mice, and IL-1β plays of iM and iDC. a crucial role in the acute host response to Mtb infection (71, 90). IL-1β augments TNF-α-stimulated Mtb killing and increases 2.4.1. T1-IFNs Mediate the Influx of iM and iDC (PGE ) production by upregulating cyclooxyge- prostaglandin E2 2 Mtb-infected mice treated with the T1-IFN-inducing compound nase-2 (COX2/PTGS2) (71, 97, 98). PGE is involved in control poly-ICLC show increased numbers of iM and iDC in the lungs, of intracellular Mtb replication but also prevents necrotic host cell −/− which are 10 times more permissive to Mtb infection than their death (99). In accordance, Ptgs2 mice, unable to produce PGE , counterparts in PBS-treated mice (72). Others confirmed that are more susceptible to Mtb infection than wild type mice, but to −/− signaling through IFNAR indeed augments the recruitment of a lesser degree than IL1 mice. Further, information on PGE in Mtb-permissive iM and iDC into the lungs (69). Mechanistically, TB is given in Box 2. IFNAR-dependent expression of the chemokine CCL2 mediates Type I interferons inhibit the expression and production of the influx of CCR2 monocytes that differentiate into iM and IL-1β and simultaneously increase the expression of 5-lipoxyge- iDC (72). Both myeloid and parenchymal cells can produce nase (5-LO), which is a competitive enzyme for COX2 in the ara- CCL2 in response to T1-IFNs, but parenchymal cells appear the chidonic acid metabolism (71, 90, 114, 115). As a result, IFNAR Frontiers in Immunology | www.frontiersin.org 6 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB expression and increase the expression of soluble antagonists for BOx 2 | The dual faces of prostaglandin e (Pge ) in tuberculosis (TB) 2 2 the IL-1 receptor (114, 132). immunity. Despite the abovementioned functional similarities between Prostaglandin E is generally considered a pro-inflammatory mediator and T1-IFNs and IFN-γ in IL-1β inhibition, mechanistic differences indispensable for the induction of fever, which is a hallmark symptom of active exist between these IFN types in mediating this effect. TB (100, 101). The anti-inflammatory effects of prostaglandin synthase (COX-) inhibitors such as NSAIDs underline this notion. However, high levels of PGE2 Ex vivo studies in human iM and iDC demonstrate that can also exert immunosuppressive effects as they stimulate alternative acti- IFN-β inhibits IL-1β production more potently than IFN-γ vation of macrophages (102), inhibit bactericidal activity (103), and promote (90, 114). One explanation might be that IFN-γ inhibits IL-10, production of IL-10 (104). Moreover, high PGE levels can stimulate the deve- while T1-IFNs induce IL-10, which contributes to the inhibition lopment of myeloid-derived suppressor cells with inhibitory effects on adaptive of IL-1β production (90, 114, 115). Additionally, an IL-10- immune cells (104, 105). Finally, PGE inhibits IL-12 production by DCs and IFN-γ production by T-cells, thereby promoting Th2/Th17 immunity (106, 107). independent inhibition of IL-1β by T1-IFNs was recently identi- In the serum and bronchoalveolar lavage fluid of TB patients, PGE levels fied (129). T1-IFNs induce cholesterol 25-hydroxylase, which were found to be elevated (71, 108, 109), and polymorphisms in the PGE2 potently reduces IL-1β transcription and broadly represses IL-1- receptor EP2 are associated with TB-susceptibility (110). Experimentally, one activating inflammasomes. In contrast, IFN-γ inhibits IL-1β mouse study showed that low PGE2 levels in the acute phase of infection by increasing intracellular nitric oxide in an iNOS-dependent are essential for iNOS-mediated control of Mtb (111). Also, PGE plays an important role during acute TB since the PGE2-producing enzyme COX2 way (120). This prevents NLRP3 inflammasome activation and competes for arachidonic acid substrate with 5-lipoxygenase, which produ- cleavage of pro-IL-1β into IL-1β. In contrast to the mechanisms ces leukotrienes and lipoxins. Hereby, PGE2 prevents necrotic cell death thus exerted by T1-IFNs, IFN-γ-induced iNOS not only limits benefiting the host (71). Opposed to the protective role of low PGE levels IL-1β-mediated inflammation but also markedly enhances the during acute disease, PGE2 levels are higher during the chronic phase of TB, and these concentrations contribute to disease by suppressing IFN-γ, bactericidal potential of iM (120). Conversely, T1-IFNs suppress TNF-α, and iNOS (111). Notably, the cellular source of PGE2 appears to differ iNOS production (90). Based on the stimulation of iNOS by between acute and chronic TB. During the acute phase of infection, inflam- IFN-γ and the inhibition of iNOS by T1-IFNs, it appears that matory myeloid cells are the main source of PGE2, while foamy macrophages iDC are more sensitive to T1-IFN signaling and iM to IFN-γ are strong producers of PGE during the chronic phase of disease (112). In when both types of interferon are present. T1-IFN-mediated line with a detrimental effect of high PGE2 levels in the chronic phase, foamy macrophages are typically associated with disease progression (113). inhibition of iNOS appears to occur primarily in iDC, since iDC −/− mice during viral infection, only expressed iNOS in IFNAR while iM appear more sensitive to IFN-γ and are the main source signaling causes a shift from COX2-mediated PGE production of iNOS in wild-type mice (131). to an increase in the 5-LO products such as lipoxin A (LXA ) When taken together, these data suggest that IL-1β inhibition 4 4 and leukotriene B (LTB ), which render cells more susceptible to by either T1-IFNs or IFN-γ has strong implications on the bacte- 4 4 necrotic cell death (71, 116). Pharmacological intervention in this ricidal potential of iM and iDC. Furthermore, T1-IFNs interfere process by administrating the 5-LO inhibitor Zileuton to Mtb- with the induction of iNOS by IFN-γ, particularly in iDC. This infected mice, improved disease outcomes during acute infection ts t fi he observation that IFN-γ only inhibits IL-1β production by −/− to similar extent as observed in IFNAR mice (71). An overview iM but not iDC in mouse TB models (90). Notably, iDC are the on the balance between IL-1β and T1-IFNs is given in Figure 2. most readily infected cells in the lungs of Mtb-infected mice (25) and are present in larger numbers than iM during Mtb infection 2.4.3. Prolonged IL-1β Signaling Causes PMN- (72, 133). Mediated Tissue Damage and Is Regulated by Both T1-IFNs and IFN-γ 2.4.4. The Interplay between T1-IFNs and IFN-γ e cr Th oss talk between T1-IFNs and IL-1β influences disease out- During direct contact with Mtb through TLRs, endogenous come in TB (71). However, this does not fully explain the harmful T1-IFN signaling through IRF3 promotes IL-12 production by effects of T1-IFNs observed in TB. Most importantly, although iDC over IL-23 (see also Figure  2; Box  3) (94, 134, 135). This IL-1β production is essential for protective immunity in the acute early IL-12 signaling is required to induce IFN-γ production by phase of disease in TB, it requires strict regulation as unchecked innate lymphoid cells (ILC) such as NK cells and possibly ILC1s IL-1β signaling in TB can result in excessive PMN-mediated tissue (136, 137). However, exogeneous T1-IFNs or T1-IFN signaling in damage (120, 123). Also, as explained in Box 2, IL-1β-mediated the absence of TLR stimulation can also inhibit IL-12 production PGE production is protective during acute disease but appears to by iDC (115, 138). This inhibition of IL-12 by T1-IFNs occurs have a detrimental effect during chronic disease. Finally, inflam- particularly through induction of IL-10 (15). T1-IFNs also inhibit matory mediators associated with continuing infection, e.g., the responsiveness of iDC to IFN-γ-mediated activation, which GM-CSF, predispose for IL-1β production over T1-IFNs by iM is required for Mtb killing. This occurs partially by reducing the and iDC (36, 94, 124–126). This reflects an increasing need over expression level of IFN-γ-receptor on the cell surface, but pri- high time to limit IL-1β-mediated inflammatory responses. regulatory phenotype in marily through induction of an IL-10 To prevent PMN-mediated inflammation caused by exces- which antimicrobial pathways by IFN-γ are not readily activated, as discussed below (90, 115, 131, 139–141). sive IL-1β signaling, the expression and production of IL-1β is inhibited not only by T1-IFNs but also by IFN-γ (90, 120). In Recent findings might explain the mechanism behind this paradox where T1-IFNs initially support IL-12-mediated IFN-γ line with this, both T1-IFNs and IFN-γ can inhibit PMN influx high (127–131). T1-IFNs and IFN-γ can both reduce pro-IL-1β gene production by NK cells but can also induce an IL-10 phenotype Frontiers in Immunology | www.frontiersin.org 7 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB FigURe 2 | inflammatory responses during acute infection in naïve inflammatory macrophages and dendritic cells. Green text indicates a beneficial host effect during Mtb infection and red indicates a detrimental effect. Mtb, Mycobacterium tuberculosis; PRR, pattern recognition receptor; STING, STimulator of INterferon Genes; TBK1, tank-binding kinase 1; IRF3, interferon regulatory factor 3; 5-LO, 5-lipoxygenase; COX-2, cyclooxygenase 2; PGE2, prostaglandin E2; EP2, 1 2 3 4 5 prostaglandin E receptor 2; ILC3, innate lymphoid cells type 3. Jayaraman et al. (97), Chen et al. (116), Shi et al. (107), Di Paolo et al. (98), Lockhart et al. (117), 6 7 8 9 10 11 12 13 Boniface et al. (106), El-Behi et al. (118), Fremond et al. (119), Mishra et al. (120), Watson et al. (81), Fleetwood et al. (94), Mayer-Barber et al. (71), Antonelli 14 15 16 17 18 et al. (72), Une et al. (121), Longhi et al. (122), Manca et al. (64), Manca et al. (65), and Mayer-Barber et al. (90). in iDC, which interferes with IL-12 production and prevents produce IFN-γ as early as 3 days post infection (154). This results high IFN-γ-mediated activation. It has been observed in different in a uniform presence of an IFN-γ-primed signature of Ly6C mouse models, including Mtb-infected mice, that T1-IFNs can monocytes in the circulation at day 6. Furthermore, IFN-γ indeed high only induce an IL-10 regulatory phenotype in monocyte- primed these monocytes toward a regulatory phenotype, as they derived DCs (iregDC) if these cells have been primed previously more effectively produced IL-10 in response to bacterial ligands by IFN-γ (43). IFN-γ-primed DCs that did not receive T1-IFN (154). We speculate that a similar mechanism of IFN-γ priming signaling differentiated into iDC that stimulated robust T-cell is likely to be involved in pulmonary infections. responses. This phenomenon of monocyte priming by IFN-γ has es Th e data suggest interplay between T1-IFNs and IFN-γ as been demonstrated to occur in the bone marrow (154). During proposed in Figure 3. T1-IFNs initially induce IFN-γ responses by gut infections, local production of IL-12 in mucosa-associated promoting IL-12 production in naïve cells as shown in Figure 2. lymphoid tissue stimulates bone-marrow-resident NK  cells to es Th e IL-12 responses stimulate IFN-γ production by ILC not Frontiers in Immunology | www.frontiersin.org 8 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB Next to their shared ability to inhibit IL-1β, an interesting BOx 3 | iL-12 or iL-23 production by dendritic cells? interplay between T1-IFNs and IFN-γ exists in TB as summarized IL-12 and IL-23 are heterodimeric cytokines composed of a common p40 in Figure  3. Two recent findings that are of particular interest subunit, coupled with either a p35 subunit in IL-12 or a p19 subunit in IL-23. high include the observation that T1-IFNs can only induce an IL-10 Both IL-12 and IL-23 are produced in particular by stimulated dendritic cells phenotype in IFN-γ-primed cells (43) and the inductive role of and to lesser degree by macrophages. The preferential production of IL-12 or IL-23 by these cells is multifactorial. Increased levels of PGE2 support T1-IFNs in early IL-12 signaling, which is required for IFN-γ IL-23 production over IL-12 (106, 107, 142). Activation of TLR2 and TLR4 priming in the bone marrow (154). Further, research into this also stimulates IL-23 production over IL-12, especially when NOD2 is simul- complex interplay between T1-IFNs and IFN-γ during early host taneously activated (143, 144). On the other hand, TLR9 and TLR3 agonists responses in TB would be highly interesting given the T1-IFN- preferentially induce IL-12 (135, 145, 146). Downstream of PRRs, activation of inducing capacities of Mtb and the shaping effect of early T1-IFN IRF 4 and 5 favor induction of IL-23, while IRF 1, 3, and 7 induce IL-12 (135, 147). In line with this, T1-IFN-mediated IRF3 activation and IFN-γ-mediated or IFN-γ signaling on the ensuing immune response. IRF-1-activation both favor IL-12 production (148, 149). IL-4 also favors IL-12 production and inhibits IL-23 production, especially 3. THe Th17 ReSPONSe iN TB in combination with IFN-γ or GM-CSF (150, 151). Finally, an important pathway that promotes IL-12 over IL-23 is ligation of the co-stimulatory molecule CD40 As discussed in the previous paragraph, T1-IFNs induce IL-12 by CD40L on activated T-cells or by agonist antibodies (152). Taken together, IL-23 is induced in the presence of pathogens and innate signaling in the production by iDC, while IL-1β induces IL-23. Other factors acute phase of infection, while onset of adaptive immunity with increased also influence production of IL-12 or IL-23 (see Box 3). IL-12 is levels of IFN-γ and/or IL-4 shifts the balance toward IL-12 (153). essential for the induction of IFN-γ responses in TB, but IL-1β is protective during acute TB despite inducing IL-23 over IL-12. Similar to the requirement of IL-12 for Th1 responses, IL-23 is only locally but also systemically, which results in IFN-γ priming essential for establishing Th17 immunity (157–159). Here, we of monocytes in the bone marrow. Once IFN-γ production is review the effect of IL-23 signaling and the Th17 response in TB. initiated, T1-IFNs mediate a regulatory function by inducing an high IL-10 phenotype in IFN-γ-primed iDC. This prevents further 3.1. introduction to the Th17 Response production of IL-12 by these cells, inhibits their activation by e Th Th17 response is distinct from classical cell-mediated Th1 IFN-γ, and results in an Mtb-permissive phenotype. immunity or B-cell-stimulating Th2 responses and is oen a ft sso- ciated with a potent inflammatory response and tissue damage 2.5. Summary: The Role of T1-iFNs in TB (159). Th17 cells display a high degree of plasticity and their abil- Several modest clinical successes have been shown with IFN-α ity to express signature markers of other T-helper lineages makes supplementation adjunct to antibiotic TB treatment (Table  1). it difficult to establish their exact role in disease. Four different However, case reports of TB reactivation under IFN-α treatment subsets of Th17  cells have been described to date with ranging without concomitant antibiotics have put T1-IFNs in a nega- inflammatory potential (160). On one side of the spectrum are tive spotlight (50–57). Furthermore, a T1-IFN transcriptional highly inflammatory and oen p ft athogenic IFN-γ/GM-CSF- signature in circulating leukocytes is associated with active TB. producing Th17.1 cells that result from prolonged IL-1β and Nevertheless, the functional role of T1-IFNs in TB patients IL-23 signaling (161). On the other side are IL-10-producing remains to be determined (62). Th17  cells, which can even transdifferentiate into regulatory Preclinical studies in mice support a detrimental role for T-cells and contribute to resolution of inflammation (162). T1-IFN in the acute phase of Mtb infection. T1-IFN signaling Despite the plasticity in cytokine production, IL-17 remains was associated with increased mortality in Mtb-susceptible mouse the hallmark cytokine of the Th17 response. Next to Th17 cells, strains and higher Mtb loads in the lungs in most studies (Table 2). γδ T-cells and ILC3 can also produce IL-17 in response to IL-23 However, it should be noted that most of these preclinical and IL-1β (27, 117, 163). IL-17 exerts its effects primarily on studies do not unequivocally support a harmful effect of T1-IFNs nearby parenchymal cells and to lesser extent on hematopoietic during the chronic phase of disease based on mortality, Mtb cells, which is distinct from Th1 and Th2 cytokines like IFN-γ and loads, or differences in adaptive immunity. IL-4 (159). In parenchymal cells, IL-17 primarily stimulates the In support of a pathogenic role of T1-IFNs during acute infec- production of the chemokines that attract PMN (164). However, tion, mycobacteria actively induce T1-IFNs by triggering cyto- it should be noted that IL-17 alone is a poor inducer of these solic PRRs. This leads to IFN-β production in an IRF3-dependent chemokines and that synergistic activation by inflammatory way. Subsequently, T1-IFNs mediate the CCL2/CCR2-dependent ligands such as IL-1β, TNF-α, or GM-CSF markedly increases migration of iM and iDC into the lungs (72). In these cells, inter- the effects of IL-17 (164, 165). ference of T1-IFNs with IL-1β and PGE as shown in Figure 2 can lead to an altered metabolism of arachidonic acids that leaves cells 3.2. The Th17 Response in Human TB more vulnerable to necrotic cell death (71). However, sustained infection IL-1β signaling itself carries the risk of excessive inflammation in TB and not only T1-IFNs but also IFN-γ inhibits IL-1β to prevent e exac Th t role of the Th17 response in human TB remains a topic of debate (13, 14, 166). Polymorphisms in genes encoding excessive PMN-mediated inflammation (120). T1-IFNs inhibit high IL-1β more effectively than IFN-γ but stimulate an IL-10 Mtb- IL-17 are associated with susceptibility to pulmonary TB, which indicates a role for this cytokine in TB (167–170). However, these permissive phenotype (72, 90). Frontiers in Immunology | www.frontiersin.org 9 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB FigURe 3 | Hypothetical interplay between type i interferons (T1-iFNs) and iFN-γ in monocyte priming and shaping of the immune response in Mtb infection. Dashed lines indicate speculations in the context of pulmonary Mtb infection; solid lines indicate shown pathways in human and/or in animal models. (1) T1-IFN induces migration of CCR2 monocytes (iMo) from the bone marrow to the lungs of Mtb-infected mice under influence of CCL2 (72). Locally, these cells + high + int develop into CD11b Ly6C inflammatory macrophages (iM) and CD11b Ly6C inflammatory dendritic cells (iDC) (43). (2) As shown in Figure 1, naïve iM and iDC can initiate either IL-1β-mediated inflammation or T1-IFN-mediated inflammation. Mtb actively triggers intracellular pattern recognition receptors to induce a T1-IFN-mediated response. (3) Additionally, iM and iDC in the naïve situation have differentiated under influence of M-CSF, which makes them more responsive to T1-IFN signaling (94). During progression of Mtb infection, GM-CSF levels rise and increase the potential for IL-1β production by iM and iDC (94, 125, 155, 156). (4) Similar to the situation in gut infection, we propose that in tuberculosis (TB) IL-12 production in the lungs stimulates IFN-γ production by bone-marrow-resident NK cells, which locally primes monocytes (154). IFN-γ priming of monocyte-derived iDC is necessary for T1-IFNs to induce a regulatory (iregDC) phenotype in iDC in the lungs (43). (5) Additionally, IFN-γ stimulates monopoiesis over granulopoiesis by granulocyte/macrophage progenitor cells (128). (6) As Mtb infection progresses and GM-CSF levels increase, iM and iDC readily produce IL-1β [see also (3)] (124, 155), which can lead to PMN-mediated inflammatory damage in TB (120). (7) IL-1β production can be inhibited in response to either IFN-γ or IFN-β through mechanistically distinct pathways that differently affect Mtb killing. (8) Signaling through IFN-α/β receptor in IFN-γ-primed iDCs induces IL-10 production (43, 115, 131), inhibits IL-12 production (115), and makes these cells unresponsive to activation by IFN-γ (43, 115, 141), which together interfere with protective immunity during acute Mtb infection. findings could not be reproduced in different demographic set- Different studies report PBMC stimulation assays with Mtb- tings (171, 172). specific antigens showing either increased or reduced Th17 Analyses of Th17 responses in peripheral blood mononuclear responses in ATB compared to LTBI (Table  3). es Th e diverse cells (PBMC) from TB patients do not show uniform results either. findings are similar to those observed in IFN-γ response assays Direct ex vivo analyses of unstimulated circulating CD4 T-cells (IGRA), in which the levels of IFN-γ oen a ft lso cannot discrimi- show that active TB (ATB) is associated with reduced frequencies nate between ATB and LTBI (176, 177). Interestingly, both Th1 of circulating Th17 cells compared to latent TB infection (LTBI) and Th17 cells appear functionally inhibited in ATB patients by a (173, 174). However, serum IL-17 levels do not differ between PD-1-mediated immunosuppressive state (178–181). In accord, ATB and LTBI, and IL-17 is undetectable in the bronchoalveolar reductions in PD-1 expression under TB treatment restored both lavage fluid during both stages of disease (174, 175). Th1 and Th17 responses (182). Frontiers in Immunology | www.frontiersin.org 10 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB TABLe 3 | iL-17 responses in patients with active TB (ATB) compared to This tendency of Th17 cells to produce IFN-γ instead of IL-17 latent tuberculosis infection (LTBi). during recall responses might explain the observation that IL-17 production during later phases of Mtb infection is dominated by increased in ATB No difference Reduced in ATB γδ T-cells rather than CD4 cells (117, 198). + + % of IL-17 CD4 T-cells When taken together, initial shaping of the local inflamma- Short Basile et al. (183) Marin et al. (184, Scriba et al. (175); tory environment by IL-17 and IL-23 during acute infection incubation 185) Perreau et al. (186) stimulates local TLS formation. This facilitates the development (0–48 h) of more robust Th1 responses by improving contact between Long Jurado et al. (187); Cowan et al. (174); Perreau et al. (186); antigen-presenting cells (APC) and lymphoid cells (Figure  4). incubation Marin et al. (184) Marin et al. (185) Heidarnezhad et al. Furthermore, Th17 cells confer protective immunity during recall (72–144 h) (188) responses by their enhanced capacity to migrate to the lungs and Ex vivo IL-17 Jurado et al. (187); Sargentini et al. Kumar et al. (192); responses compared to other CD4 T-helper cell stimulate Tfh production Xu et al. (189) (190); Cowan et al. Nunnari et al. (193); populations. (174); Kim et al. Bandaru et al. (182) (191) Only in MDR-TB. 3.4. The Th17 Response, PMN, and inflammatory Damage Taken together, systemic Th17 responses in TB patients dem- IL-17 stimulates granulopoiesis in the bone marrow and increases onstrate similar variability as observed for IGRA studies. Both PMN influx to the site of infection by inducing G-CSF, CXCL1, are unable to distinguish ATB from LTBI. How these systemic CXCL3, and CXCL5 expression by parenchymal cells in mice responses relate to local host responses in the lungs has not been or G-CSF and IL-8 in humans (159). These effects of IL-17 are characterized in TB patients. markedly enhanced through synergistic activation by inflamma- tory mediators such as IL-1β, TNF-α, or GM-CSF (164, 212, 213). 3.3. Preclinical Studies in Mice Support a In this regard, IL-17 is not a strong inducer of inflammation by Protective Role for iL-23 and iL-17 in TB itself, but rather amplifies preexisting inflammation. This IL-17- Based on mortality and mycobacterial loads, studies in Mtb- mediated “inflammatory boost” can positively shape adaptive infected mice support a protective role for IL-23 and IL-17 in TB, immunity, but prolonged or repeated antigen exposure can also but only during later stages of disease (Table 4). lead to PMN-mediated pathological inflammation (214). Since Interestingly, these late protective effects result from effects IL-17 signaling is inevitably linked to PMN influx, the role of induced during the initial phase infection (142, 195). This is due PMN in TB provides an additional perspective on the effects of to the essential roles of IL-23 and IL-17 in the local formation of IL-17 signaling in TB. tertiary lymphoid structures (TLS) (199, 200). es Th e structures are Review of available literature on the role of PMN in TB yields a formed during early infection but can persist for longer periods of complex picture with seemingly conflicting effects (14, 166, 215). time and are associated with protective immunity in Mtb-infected In patients with active TB, PMN are the predominantly infected mice (199, 201) (Table 4; Figure 4). Furthermore, IL-17 and IL-23 cells in the airways and provide a permissive site for a burst of increase the expression of the chemokine CXCL13 (194, 197). active mycobacterial replication prior to transmission (216). On This chemokine stimulates the influx of TLS-associated CXCR5 the other hand, PMN from healthy individuals, especially when follicular helper (T )-cell, which facilitate optimal localization of fh stimulated with TNF-α, show a strong bactericidal effect (217). effector T-cell populations within the lung parenchyma, thereby In preclinical TB models, highly susceptible mouse strains such promoting efficient T-cell-dependent macrophage activation and as I/St, CBA/J, or DBA/2 show an enhanced influx of apoptosis- intracellular Mtb killing (194, 201). resistant, highly phagocytic neutrophils that negatively aeff ct On account of their ability to induce TLS formation, boosting survival compared to more TB-resistant C57BL/6 and BALB/c IL-23 and IL-17 production is also an interesting strategy for mice (218–220). Moreover, PMN are poor producers of essential vaccine-induced protection against TB. In this regard, IL-17 pro- cytokines such as IL-1α/β and IL-12p40 in the anti-TB response duction by Th17 cells during recall responses is indeed dependent (90, 221). These effects in preclinical models primarily suggest on IL-23 and could reduce mycobacterial loads in the lungs of a negative contribution of PMN to acute disease. However, Mtb-infected mice (210). Th17 cells preferentially migrate to the increasing evidence suggests a supportive role for PMN in pro- lungs and are better contained in the lungs compared to Th1 cells tective immunity. PMN can indirectly augment IL-1β-mediated upon adoptive transfer to naïve mice (210, 211). The develop- inflammatory responses in macrophages aer co ft ntact with Mtb mental flexibility of Th17 cells is illustrated in experiments where (202, 204, 205). Also, and consistent with Th17 responses, PMN Mtb-antigen-primed Th17 cells have been adoptively transferred play an essential role in generation of protective recall responses to naïve mice (210). Initially, these Th17  cells produce IL-17. in Mtb-infected mice (195, 206, 222). Early, but not late PMN However, upon recall immunity against Mtb, they primarily pro- recruitment is essential for IL-17-mediated long-term control of duce IFN-γ, with or without IL-17. Paradoxically, the latter switch Mtb infection (195). This can be explained by the finding that results in a less effective reduction in bacterial loads compared to DCs that acquire Mtb through uptake of infected PMN are better IL-17-producing Th17 cells that are adoptively transferred from able to activate T-cells (203, 222). The importance of this mecha- −/− IFN-γ mice. nism is recently highlighted in Mtb-infected mice, showing that Frontiers in Immunology | www.frontiersin.org 11 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB TABLe 4 | Th17-related effects in preclinical tuberculosis (TB) studies in mice. Mice intervention Mtb strain, route Survival Mtb load (vs. wild-type mice) immunological effect Reference (age, weeks) B6 (6–12) IL23 H37Rv (100 CFU), No data No difference in lungs No IL-17-producing cells in lungs up Khader et al. (158) −/− p19 aerosol 1 log higher Mtb load in spleen at to day 150 day 150 B6 (6–12) IL23 H37Rv (100 CFU), No data Day 120 and onward, 0.5–1 log Reduced no. of B-cell follicles at day Khader et al. (194) −/− p19 aerosol higher Mtb load in lungs 200 (Cxcl13 mediated) Strongly impaired IL-17, IL-22 production in lungs up to day 250 −/− B6 (6–12) IL22 H37Rv (100 CFU), No data No effect up to day 200 Suboptimal B-cell follicle development Khader et al. (194) aerosol (Cxcl13-mediated) B6 (6–9) IL-17 H37Rv Higher 1.5 log higher Mtb load at week 12 Impaired cell recruitment (PMN, Freches et al. (195) −/− 3  RA (1.10 CFU), i.t. mortality and week 20 in lungs lymphocytes, Mo/DC) (median Increased IL-1β survival: 18 Decreased TNF-α, IL-6 and IL-10 vs. 35 weeks) B6 (6–12) IL-17 H37Rv (100 CFU), No data No effect up to day 200 Suboptimal B-cell follicle development Khader et al. (194) −/− RA aerosol (Cxcl13-mediated) −/− B6 (8–12) IL-17 H37Rv No data 1.5 log higher Mtb load Reduced no. of granulomas at day 28 Okamoto Yoshida (1.10  CFU), i.t. et al. (196) −/− B6 (6–8) IL-17 HN878 (100 CFU), No data 1 log higher Mtb load in lungs at Infection with HN878 showed robust Gopal et al. (197) aerosol day 30 production of IL-1β through TLR2, 0.5 log higher Mtb load in lungs at which supported increased IL-17 day 60 production compared to H37Rv and CDC1551 −/− B6 (6–8) IL-17 H37Rv, CDC1551 No data No difference at day 30 and day 60 Gopal et al. (197) (100 CFU), aerosol −/− B6 (8–12) IL-17 H37Rv Higher 1.5 log higher Mtb loads in lungs at Impaired granuloma formation, γδ Umemura et al. (198) 3  (1.10 CFU), i.t. mortality day 30, 1 log higher Mtb loads at day T-cells primary source of IL-17 60 and day 120 Red text indicates a harmful effect to the host; CFU, colony forming units; IL-17RA, IL-17 receptor A; i.t., intratracheal instillation. PMN-depletion during vaccination prevented the generation of of recall responses, or initiate resolution of inflammation in the specific Th1 and Th17 responses (206). absence of inflammatory or microbial stimuli. A second emerging protective role of PMN is their contribu- tion to initiating inflammation resolution (223). In mouse TB 3.5. Summary: The Role of Th17 models, PMN are the main producers of IL-10 in the lungs and can dampen inflammatory damage (224). In this regulatory role, immunity in TB PMN inhibit Th17 responses but do not interfere with IFN-γ- e r Th oles of IL-23 and IL-17 in TB are more subtle than the effects of Th1-related cytokines or T1-IFNs. Patient data are mostly lim- mediated Th1 immunity due to relative insensitivity of Th1 cells to IL-10 (224, 225). Another regulatory effect of PMN concerns ited to studies in PBMC. These show inconclusive results that are possibly confounded by the dynamics and heterogeneity of the their apoptosis and subsequent phagocytosis by macrophages in the absence of extracellular Mtb. This inhibits IL-23 production Th17 response, which can range from highly pro-inflammatory high M2c IFN-γ/GM-CSF-producing Th17.1 cells to IL-10-producing by these macrophages and induces a regulatory IL-10 phenotype under influence of IL-17 and IL-10 (see Figure 4) (226, regulatory Th17 cells. 227). IL-17 can further contribute to this process by attenuating Preclinical mouse TB models provide evidence for a protective the anti-apoptotic effect of GM-CSF on PMN and by stimulating role of the Th17 cytokines IL-23 and IL-17 in TB. These protec- PMN apoptosis (228, 229). tive effects become apparent in the chronic phase of infection Taken together, PMN recruitment to the site of infection but result from IL-23/IL-17-mediated effects in the earlier, acute is largely dependent on IL-17, but only in synergy with innate phase of infection. This is associated with early protective effects inflammatory cytokines such as IL-1β. Locally, these recruited of IL-1β, which is a strong inducer of IL-23 and IL-17 (Figure 4). PMN contribute to inflammation if pathogens are still present, Mechanistically, evidence for the protective effects of IL-17 and improve dendritic cell function, and contribute to the formation IL-23 primarily points toward their role in the development of Frontiers in Immunology | www.frontiersin.org 12 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB FigURe 4 | The iL-23/iL-17 axis in acute tuberculosis. (1) When inflammatory dendritic cells (iDC) recognize Mtb through membrane-bound toll-like receptors, they can secrete IL-1β, IL-23, and prostaglandin E2 (PGE ) (see Figure 1). This occurs more efficiently if iDC are activated through contact with Mtb-infected PMN, which also stimulates their migratory capacity to tertiary lymphoid structures (TLS) and promotes recall immunity (202–206). (2) The combination of IL-1β and IL-23 induces IL-17 production by γδ T-cells and possibly ILC3 (27, 117). (3) Activation of parenchymal cells by IL-17 in combination with IL-1β or other inflammatory mediators ultimately results in PMN influx. (4) PMN contribute to inflammation when stimulated by extracellular Mtb or inflammatory cytokines. (5) Activated PMN readily cause tissue damage through production of ROS and proteases; this effect is suppressed by activated iDC in a PGE -dependent way (112, 207, 208). (6) IL-23 and IL-17 stimulate the local production of CXCL13 by stromal cells (194, 199). This promotes TLS formation and follicular helper T-cell migration to the site of infection. (7) CD40 ligation in the interaction between (i)DC and CD4 T-cells is a strong stimulus for IL-12 production over IL-23 (Box 3) and leads to Th1 formation and IFN-γ production. (8) IFN-γ inhibits IL-1β production and shifts IL-23 production to IL-12, thus inhibiting IL-17 production and reinforcing the Th1 response (209). (9) In the absence of inflammatory stimuli, PMN can produce IL-10 and undergo apoptosis. Phagocytosis of apoptotic PMN induces an IL-10-producing regulatory M2c phenotype in macrophages and further contributes to resolution of inflammation. TLS during the acute phase of disease, which provides protective cells to protective immunity in TB is increasingly recognized effects during later stages (199, 230). Additionally, IL-23 and (206). Early, but not late PMN recruitment is essential for IL-17- IL-17 induce CXCL13 expression that mediates the influx of mediated long-term control of Mtb infection (195) and DCs that TLS-associated T cells. TLS and T responses facilitate optimal acquire Mtb through uptake of infected PMN are better able to fh fh interactions between adaptive and innate immunity, contribute activate T-cells than DCs that directly interact with Mtb them- to granuloma formation, and improve the quality of T-cell recall selves (203, 222). The ability of IL-17 to induce the production responses in TB (201). In TB patients, TLS have also been associ- of PMN-attracting chemokines in parenchymal cells is markedly ated with immune control, but more in-depth research is needed improved when IL-17 signals in synergy with inflammatory to establish their exact functional role and contribution to protec- mediators such as IL-1β, which again indicates synergy between tive immunity (201). IL-1β and IL-17 responses during acute TB. Prolonged activation Next to TLS formation and function, IL-23 and IL-17 mediate of IL-1β and IL-17 responses can lead to massive accumulation the influx of PMN into the lungs and the contribution of these of PMN, and their local necrotic death can also be damaging to Frontiers in Immunology | www.frontiersin.org 13 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB the host. However, in the absence of inflammatory stimuli, PMN In accordance, pDC have been found to be a major source of are an important source of IL-10 in the lungs and can initiate T1-IFNs in SLE (247, 248). Immune complexes (IC), consisting resolution of inflammation (Figure 4). of antibodies bound to self-DNA, are a major trigger for IFN-α production by pDC in AID (249). However, pDC are not acti- vated by self-DNA under steady state conditions, which indicates 4. T1-iFNs, THe Th17 ReSPONSe AND that additional stimuli are required. One such stimulus is the THeiR iNTeRACTiONS iN AUTOiMMUNe PMN-derived antimicrobial peptide LL37 (249), which convert DiSeASe inert self-DNA into a potent activator of endosomal TLR9 (250). Another stimulus is the nuclear protein high mobility group box Autoimmune diseases comprise a wide range of organ-specific 1 (HMGB1) protein, which is secreted by activated myeloid cells and systemic disorders. Most systemic AID are considered clas- and passively released by necrotic, but not apoptotic cells (251). sical B cell-mediated diseases, typified by circulating autoreactive HMGB1 binds DNA, and the formed complexes bind with high antibodies against intracellular self-antigens. The clinical presen- affinity to receptor for advanced glycation end-products, which tation of different AID varies, but evidence from genome-wide facilitates internalization into the endosome where TLR9 can be association studies points toward common immunogenetic activated (249). Extracellular HMGB1 also triggers the recruit- mechanisms, as many systemic AID share disease-associated ment of PMN and stimulates their formation of neutrophil genes (231). Another trait particularly shared amongst different extracellular traps (NETs) (252). NETs contain large amounts of antibody-driven AID is the expression of a T1-IFN signature in nucleic acids and LL37 and are also a major driving factor behind both blood- and disease-ae ff cted tissue (232–234), the strength chronic pDC activation and IFN-α production in SLE (253). of which generally correlates with disease activity and severity It deserves mention that NET formation is driven by reactive (235–238). Vice versa, T1-IFN immunotherapy as treatment oxygen species (ROS), which in PMN are particularly produced for other diseases is known to cause symptoms similar to those by NADPH oxidase and subsequently processed by myeloper- observed in AID, such as development of psoriatic lesions in MS oxidase (254). Paradoxically, despite the capacity of NETs to or hepatitis C-infected patients (239, 240). induce T1-IFNs and the pathogenic role of T1-IFNs in SLE, T-cells also have a major impact on the development and NADPH oxidase appears to be protective in SLE (255). Lupus- progression of AID and increasing evidence points toward prone mice deficient in NADPH-oxidase develop more severe crucial involvement of the Th17 response in the pathogenesis SLE (255). Moreover, autoimmunity with T1-IFN signatures can of multiple AID (160, 241). Th17  cells have been shown to be still develop in individuals with chronic granulomatous disease, critical in the pathogenesis of MS and rheumatoid arthritis (RA) who lack NADPH-oxidase activity (256). This seeming con- (19, 160). However, Th17  cells have also been associated with tradiction has been partially explained by the observation that disease severity in AID characterized by a T1-IFN signature, such IgG autoantibody-mediated NETosis, which is most relevant in as systemic lupus erythematosus (SLE) (20, 233, 242, 243). Since SLE, is specifically reliant on mitochondrial ROS, while NETosis T1-IFN signatures and Th17 responses are both associated with induced by, e.g., TLR4 signaling is NADPH dependent (256). disease in AID, the question arises whether these two pathways In line with this, NETs from SLE patients have been shown to act in concert to sustain and amplify autoimmune responses, contain mitochondrial DNA (256). Thus, the way NETs are or control each other (20, 21, 244). Therefore, we will discuss induced, and the type of DNA that is present on NETs probably below the involvement of the T1-IFN and Th17 responses in AID also influences their ability to induce T1-IFNs and their role in individually as well as their interaction. We refer readers who are disease. familiar with the contributions of T1-IFN and Th17 in AID to Taken together, TLR9-mediated IFN-α production by pDC in continue at Section 4.3 where we discuss the interaction between response to IC and NETs appears the major driving factor behind these pathways. T1-IFN production in autoantibody-mediated AID. Additionally, the way NETs are induced and the type of DNA present on NETs 4.1. The Contribution of T1-iFNs to the can influence disease outcomes. Pathogenesis of AiD Most insight into the role of T1-IFNs in the pathogenesis of AID 4.1.2. Disease-Promoting Effects of T1-IFN in AID has been obtained in SLE, which was the first disease in which Type I interferons exert a detrimental effect in AID through dif- a T1-IFN transcriptional signature was identified in 2003 (235). ferent pathways. In monocyte-derived cells, T1-IFNs stimulate Since then it has become clear that 60–80% of adult SLE patients maturation, increase phagocytic capacities (257), and increase and nearly 100% of pediatric SLE patients express a T1-IFN sig- the expression of co-stimulatory molecules (258). Also, T1-IFNs nature in their blood (245). Several mechanisms through which have a direct stimulating effect on T-cells. Together, these effects T1-IFNs contribute to disease in SLE, outlined below, have been promote the generation of autoreactive T-cells, which support elucidated. autoreactive B-cell responses (257, 259). At cytokine level, T1-IFNs can induce the production of B-cell 4.1.1. Induction of T1-IFNs in AID activating factor (BAFF) by myeloid cells (238, 260, 261). BAFF Specifically IFN-α appears to play a central role in SLE pathogen- induction confers a significant proportion of T1-IFN-mediated esis (245, 246). As mentioned in Section 2.3 IFN-α is produced damage in SLE as supported by the observation that IFN-α in an IRF7-dependent way by pDC and other myeloid cell types. administration induces disease in SLE-prone mice but fails to Frontiers in Immunology | www.frontiersin.org 14 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB do so in B-cell-deficient and BAFF-deficient mice on the same Th17.1 cells (161). These cells can also switch their chemokine + + background (262). BAFF plays a central role in the development receptor profile and become CCR2 instead of CCR6 (161). and selection of autoreactive B-cells (260). In line with this, Expression of CCR2 by Th17.1 cells can contribute to their increased BAFF expression correlates with disease severity in inflammatory potential as it can divert their migration to sites SLE (21, 260, 263). BAFF also induces class switch recombina- without concomitant influx of regulatory T-cells, which depend tion in B-cells, leading to preferential expression of IgG and IgA on CCR6 for their migration (278). over IgM, which is important for Fc-receptor-mediated NETosis Mechanistically, it was shown in a mouse EAE model that induction in PMN (264). The clinical relevance of BAFF in SLE GM-CSF exerted its pathogenic effector function by stimulating pathogenesis is illustrated by the current use of belimumab, a IL-1β production by monocyte-derived cells (279). This suggests monoclonal antibody against BAFF, as treatment for SLE (265). a positive inflammatory feedback loop, since IL-1β in turn pro- Interestingly, targeting BAFF is effective in SLE patients, while motes IL-23 production and development of Th17.1 cells (118). B-cell depleting therapies using CD-20-targeting rituximab show A similar pathogenic Th17.1 response is observed in RA, which disappointing results in phase III clinical trials (266, 267). This was the first AID in which IL-1β inhibition was approved for suggests effector functions of BAFF other than B-cell activation. clinical use (280). Also, regarding the distinction between Th17 In this regard, BAFF can act as a co-stimulatory molecule for and Th17.1 responses in RA, it should be noted that anti-GM-CSF T-cells and promote Th17 development (268, 269). BAFF can therapy shows more promise than anti-IL-17 in clinical phase I/ also directly activate plasma cells, which are not depleted by II trials (160, 281). rituximab (270, 271). 4.2.2. The Contribution of IL-17-Producing Th17 Cells to AID Pathogenesis 4.2. The Contribution of Th17 in the Next to GM-CSF-secreting Th17.1 cells, regular IL-17-producing Pathogenesis of AiD Th17 cells also have been identified as pathogenic in other AID. 4.2.1. GM-CSF-Secreting Th17.1 Cells This is best exemplified by the clinical successes of targeting Pathogenic effects of Th17-mediated immunity in AID have IL-17 in psoriasis (282). Th17-associated pathogenic effects in been studied most detailed in MS and RA and their respective SLE also appear to be driven by IL-17 rather than GM-CSF (21, mouse models, experimental autoimmune encephalitis (EAE), 283). This is further supported by the specific contribution of and collagen-induced arthritis (160, 242). MS was long believed PMN to disease in SLE, which is dependent on IL-17, opposed to to be primarily driven by an IL-12/Th1 response, but this concept GM-CSF that primarily influences the inflammatory potential of was challenged by observations in the EAE mouse model for monocytes in MS and RA. MS showing that the IL-23p19 subunit instead of IL-12p35 (see Box  3) caused disease (272). In addition, the classic cytokines 4.3. interactions between T1-iFNs and the of Th1 and Th17 immunity, i.e., IFN-γ and IL-17, respectively, Th17 Response in AiD were found dispensable in EAE and instead GM-CSF appeared Systemic lupus erythematosus and other autoantibody-mediated to be the effector cytokine responsible for IL-23-induced AID show a pathogenic role for T1-IFNs, while T-cell-mediated encephalopathy (118). Notably, while most studies agree on a AID, such as MS, are driven primarily by GM-CSF-stimulated central pathogenic role for GM-CSF in MS, conflicting results are IL-1β production. With the functional dichotomy of IL-1β and reported regarding its cellular source (19, 273–275). One study T1-IFNs in mind, as shown in Figure 2, MS and SLE seem to be shows that GM-CSF expression in MS patients is promoted by opposite ends of the disease spectrum in AID instead of dem- the IL-12/T-bet/Th1 axis, instead of IL-23 as observed in mouse onstrating interactions between T1-IFNs and the Th17 response. EAE (273). Other publications report that B-cells are a major However, the existence of different Th17 subsets might explain source of GM-CSF and specifically act in concert with Th17 cells this seeming disparity and suggest roles for GM-CSF-producing (274, 276). In accord with these discrepant results, MS is shown Th17.1 cells in MS and regular IL-17-producing Th17 cells in SLE. to be a heterogeneous disease that can be driven by either Th1 or Both Th17 responses interact differently with T1-IFNs as will be Th17 immunity (242), which also has implications for therapy as discussed here. We identify three relevant interactions: (1) Th17.1 will be discussed in Section 4.3.1. responses are fueled by T1-IFN-stimulated influx of CCR2 One interesting observation in this regard is the development inflammatory monocytes; (2) a pathological IL-17/T1-IFN/BAFF of “hybrid” Th17.1 cells that express markers of both Th17 cells axis driven by NET-forming PMN; and (3) Th17 immunity and T-cells in both mice and man do not and Th1 cells. Naïve CD4 + T1-IFNs collaborate in the generation and function of TLS. An express the IL-23 receptor and can either differentiate into T-bet overview of these pathways is presented in Figure 5. Th1  cells under influence of IL-12 or differentiate into CCR6 Th17 cells under influence of IL-6 and TGF-β (161). These IL-6/ TGF-β-differentiated Th17 cells have low inflammatory potential 4.3.1. T1-IFNs Can Contribute to and are prone to adopt an IL-10-producing regulatory phenotype. Th17.1-Mediated AID However, IL-6 also induces STAT3-dependent upregulation of Among MS patients treated with IFN-β, approximately IL-23 receptor (277). Subsequent (re)activation of such IL-6- 30–50% do  not respond favorably to treatment (284). It was shown that IFN-β suppresses Th1-mediated inflammation in primed Th17 cells by IL-23 increases Th1-associated T-bet expres- sion and generates inflammatory IFN-γ/GM-CSF-producing MS but is ineffective  and may even exacerbate Th17-mediated Frontiers in Immunology | www.frontiersin.org 15 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB FigURe 5 | interactions between type i interferons (T1-iFNs) and Th17 immunity in autoimmune diseases. The color grading in the figure indicates the level of involvement of either Th17 immunity or T1-IFN-associated signaling. (1) T1-IFNs, primarily produced by plasmacytoid dendritic (pDC) but also by inflammatory dendritic cells (iDC) and PMN, prime the latter cells toward a T1-IFN/B-cell activating factor (BAFF)-producing phenotype, promote NETosis by PMN and stimulate monocyte migration by inducing CCL2 production. (2) BAFF activates B-cells, stimulates tertiary lymphoid structures (TLS) formation together with CXCL13, directly promotes Th17 differentiation (not shown), and stimulates the release of IL-1β by iDC. (3) TLS facilitate optimal interaction between activated B-cells and antigen-presenting cells (APC), while necrosis, neutrophil extracellular traps, and T1-IFN increase the chance that these APC present self-antigens. Subsequent germinal center (GC) reactions within these TLS result in B-cells differentiating into plasma cells that produce large quantities of autoantibodies. These autoantibodies can mediate tissue damage and sustain a self-amplifying loop by inducing NETosis through binding the Fc-receptor on PMN. B-cells can also contribute to Th17 immunity by their ability to secrete IL-6 and GM-CSF (not shown and uncertain if this is BAFF dependent). (4) NETs trap antibodies. This facilitates their Fc-receptor-mediated internalization by pDC in which they stimulate T1-IFN production through endosomal TLR9 activation. Circulating NETs also stimulate IL-1β production by iDC and can mediate tissue damage. (5) In a pro-inflammatory feedback loop, IL-23 stimulates the development of GM-CSF- producing Th17 cells (Th17.1), which in turn, together with BAFF and/or NETs stimulate an inflammatory phenotype in iDC. (6) IL-1β and IL-23 stimulate IL-17 production by γδ T-cells, while concomitant stimulation with IL-1β and TNF-α is required for IL-17-induced G-CSF and chemokine production in parenchymal cells. (7) IL-1β and TNF-α activate PMN to release reactive oxygen species (ROS) and proteases that cause tissue damage. Furthermore, GM-CSF increases longevity of PMN (not shown). Finally, the priming of PMN and monocytes prior to entering the site of disease is important for their eventual effector function. For monocytes this is shown in more detail in Figure 3. u Th s, a strongly pro-inflammatory condition is created in Th17.1- inflammation  (19). This  is one of the first studies that report a mediated MS. Since regulatory T  lymphocytes rely on CCR6 detrimental interaction between T1-IFNs and Th17 responses. rather than CCR2 (279), recruitment of these anti-inflammatory Given the importance of Th17.1 cells in MS, this negative outcome cells does not appear to hold pace with the influx of inflammatory might be explained by the observation that IFN-β therapy in MS monocytes and Th17.1 cells in MS. increases CCL2 production (285). Expression of this chemokine in the brain recruits inflammatory CCR2 monocytes as well as Th17.1 cells, which switch their chemokine receptor profile from 4.3.2. A Pathological IL-17/T1-IFNs/BAFF Axis in AID + + CCR6 to CCR2 upon terminal differentiation (161). Moreover, IL-17 induces PMN influx through induction of G-CSF and Th17.1 cells stimulate IL-1β production in CCR2 monocytes chemokines (see Section 3.4), which contribute to the produc- (279, 286). Inflammatory monocytes may differentiate locally tion of IFN-α by pDC via the NETosis process (see Section 4.1.1). into dendritic cells further stimulating Th17 responses (287). However, increasing evidence suggests a more prominent Frontiers in Immunology | www.frontiersin.org 16 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB contribution of IL-17 and PMN to T1-IFN-mediated disease in inflammation. An overview of these interacting pathways is shown in Figure 5. SLE. First, besides being major inducers of IFN-α production by pDC upon NETosis, PMN also appear to be a significant source of IFN-α themselves (288, 289). This was related to their sheer num- 5. iNTeRACTiONS BeTweeN T1-iFNs AND bers, as circulating pDC were 27 times more efficient in secreting Th17 iMMUNiTY iN TB IFN-α, but PMN were 100 times more frequent (289). Second, both T1-IFNs and IL-17-induced G-CSF prime PMN for NETosis In the previous section, we have outlined how T1-IFNs and (250, 290). In accord, circulating PMN of SLE patients are also the Th17 immunity interact in AID (illustrated in Figure  5). These main cells expressing the transcriptional T1-IFN signature and interactions primarily concern (1) Th17.1 responses fueled by release more NETs than PMN from healthy individuals (250, 253, T1-IFN-stimulated influx of CCR2 monocytes; (2) The IL-17/ 288, 289, 291, 292). Thirdly, T1-IFNs stimulate BAFF produc- T1-IFNs/BAFF axis driven by NET-forming PMN; and (3) syn- tion, which is essential for T1-IFN-mediated pathogenic effects ergism between Th17 immunity and T1-IFNs in TLS formation in mouse SLE (261, 262, 293). It is recently shown that IL-17 and function. In this section, we assess the relevance of these also induces BAFF production and that IL-17-driven, G-CSF- three pathways in TB based on cell types and effector molecules dependent PMN recruitment drives plasma cell responses during involved. Each subsection contains a part of Figure  5, supple- emergency granulopoiesis in a BAFF-dependent way (271). Also, mented with relevant finding and outstanding questions in TB. therapeutically administered G-CSF, which is physiologically induced by IL-17, increases BAFF production by PMN (294). 5.1. Th17.1 Responses in TB es Th e interactions indicate a prominent role for IL-17- Studies in MS and RA emphasize the difference between GM-CSF/ mediated PMN influx in T1-IFN-production and induction in IFN-γ-producing Th17.1 cells and regular IL-17-producing AID and synergistic induction of BAFF production by IL-17 and Th17  cells. e f Th ormer primarily increase the inflammatory T1-IFNs. In support of this, IL-17 and Th17 cells are associated potential of monocytes (Figure  6), while the latter are more with disease severity in SLE to similar extent as T1-IFNs (20, closely associated with PMN. Data on subtypes of Th17 cells and 21, 241, 244). In turn, BAFF can promote Th17 responses (268, particularly Th17.1 cells in human TB are limited. One study 269). This further suggests an inflammatory loop with a central shows that circulating GM-CSF T-cells are not increased in ATB role for PMN in which IL-17, T1-IFNs, and BAFF continuously compared to LTBI, but it is unclear if this concerns Th17.1 cells increase each other’s production and contribute to autoantibody- or Th1  cells (309). Interestingly, GM-CSF production by both mediated responses. granuloma-associated T-cells and circulating CD4 T-cells in TB patients only occurs aer m ft ycobacterial antigen stimulation 4.3.3. T1-IFNs, Th17 Responses, and TLS in AID (309, 310). In mice, adoptively transferred Mtb-primed Th17 cells Finally, T1-IFNs and Th17 responses converge onto the develop- ment and functioning of TLS. In these structures, T cells support fh germinal center (GC) reactions in which B-cells differentiate into antibody-producing plasma cells and memory cells (295). As expected from their function, TLS and T cells are essential com- fh ponents in the pathogenesis of multiple autoantibody-mediated AID (296–303). The cytokines IL-17 and IL-22 secreted by ILC3, γδ T-cells and Th17  cells are required for local TLS formation (199, 230, 304). T1-IFN- and IL-17-induced BAFF promote the formation and integrity of GCs within TLS and stimulate T fh development (305, 306). T1-IFNs directly induce the expression of the T -markers CXCR5 and PD-1 on T cells (307, 308). Also, fh T1-IFNs promote the survival of aberrantly selected B-cells in the GC reactions during SLE directly and indirectly through BAFF induction as discussed in Section 4.2.2. Thus, it appears that by stimulating TLS development, the Th17 response facilitates FigURe 6 | Th17.1 responses in tuberculosis (TB). (1) Type I interferons an environment that promotes selection of autoreactive B-cells (T1-IFNs) induce CCL2 production in parenchymal cells and MDM, but not under influence of T1-IFNs and BAFF. + GMDM. This induces the influx of CCR2 monocytes that mediate Taken together, several lines of evidence exist for interac- detrimental effects in TB as Mtb-permissive cells develop upon T1-IFN stimulation. (2) GM-CSF increases IL-1β production, limits responsiveness to tions between the Th17 response and T1-IFNs in systemic AID. T1-IFNs, and increases Mtb-killing potential. However, the exact cellular Current data support a scenario in which Th17 immunity fuels source of GM-CSF in TB is unknown. (3) Patients with active TB overexpress T1-IFN-related pathology by mediating PMN influx and driving TGF-β, which may drive Th17 development over Th17.1 in the presence of TLS formation, which facilitates T1-IFN/BAFF-mediated plasma IL-1β and IL-23. Dotted lines implicate mechanisms shown in autoimmune cell responses and autoantibody production. In turn, T1-IFNs diseases that have not been confirmed in TB. Outstanding questions: (1) What is (are) the cellular source(s) of T1-IFNs in TB? (2) What is the ratio can support pathogenic Th17.1 responses in AID by driving the between different Th17 subsets in TB? (3) Do T-cells contribute to GM-CSF + + influx of CCR2 inflammatory monocytes and potentially CCR2 production in TB? Th17.1 cells themselves, which locally drive IL-1β mediated Frontiers in Immunology | www.frontiersin.org 17 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB that produce IL-17 upon transfer, predominantly produce IFN- However, elevated TGF-β levels in TB patients suggest a limited γ upon subsequent contact with Mtb, which is suggestive of a contribution of Th17.1 cells to disease, as TGF-β favors the devel- Th17.1 phenotype (210). opment of regular IL-17-producing Th17 cells. Regardless of its Th17.1 cells in AID result from prolonged innate IL-1β and cellular source, preclinical TB studies support a protective role IL-23 signaling. With regard to the role of IL-1β and IL-23 in for GM-CSF during acute infection. GM-CSF causes monocytes human TB, IL-1β is essential for the expansion of both IFN-γ IL- to differentiate into cells with decreased T1-IFN responsiveness + + + 17 Th17 cells and IFN-γ IL-17 Th17 cells (311, 312). IL-23 pro- and increased Mtb-killing potential compared to their M-CSF- + + motes the development of IFN-γ IL-17 Th17 cells but promotes differentiated counterparts. However, during chronic Mtb infec- − + IFN-γ IL-17 Th17 cells if TGF-β is concomitantly present (312). tion, high GM-CSF levels appear detrimental as they stimulate Since active TB is associated with elevated TGF-β levels (178, 313, foamy macrophage development and inflammation. 314), it is possible that Th17.1 cell differentiation does not play a major role, but this remains to be demonstrated. 5.2. The iL-17/T1-iFNs/BAFF Axis in TB Th17.1-derived GM-CSF exerts a pathogenic effect in AID by In the previous paragraph, it was discussed that regular IL-17- stimulating IL-1β production in CCR2 monocytes. Although producing T-cells are more likely to play a role in TB than Th17.1 the role of Th17.1 cells in TB is uncertain, other cells such cells. Opposed to Th17.1 cells, regular Th17 cells exert their effect as NK  cells and Th1  cells can also produce GM-CSF in TB, primarily through PMN instead of CCR2 monocytes in AID. and during the course of infection, GM-CSF levels progres- Particularly in SLE, this was shown to be part of a pathogenic axis sively increase in the lungs of Mtb-infected mice (125, 315). together with T1-IFNs and BAFF. The roles of T1-IFNs and IL-17 The functional role of GM-CSF is of interest in TB, because in TB have been discussed already in Sections 2 and 3. In this it importantly impacts on CCR2 monocytes, which play a section, we assess the roles of the other components of the IL-17/ central role in T1-IFN-mediated pathogenic effects. T1-IFNs T1-IFNs/BAFF axis in TB, which include PMN-derived NETs, stimulate the influx of inflammatory CCR2 monocytes but pDC, and BAFF (Figure 7). inhibit their IL-1β production and stimulate their differen- tiation into Mtb-permissive cells (see Figure  3). In contrast, GM-CSF is protective during acute TB, which is in line with the protective effects of IL-1β in this phase of disease. Mice deficient in GM-CSF succumb rapidly to infection due to their inability to mount Th1 responses (316, 317). Transgenic mice that overexpress GM-CSF in the lungs but are GM-CSF-deficient in all other organs can develop Th1 responses, but still succumb to infection more rapidly than wild-type mice due to their inability to develop a normal granulomatous response (316, 317). Evidence from in  vitro studies suggests that GM-CSF exerts its protective effect in TB by countering the effects of T1-IFNs in CCR2 monocytes (36, 94). Under physiological conditions, monocytes differentiate under influence of M-CSF into monocyte-derived macrophages (MDM). These MDM low have a CCR2 phenotype, readily produce CCL2 and IL-10 in response to T1-IFNs, and have a low Mtb-killing capacity (94, 156, 318, 319). Conversely, monocytes that differentiate high under influence of GM-CSF (GMDM) are CCR2 , relatively unresponsive to T1-IFN signaling, produce small amounts of CCL2 and IL-10, and have better Mtb-killing capacities than MDM in response to activation by IFN-γ (36, 126). e r Th elative unresponsiveness of GMDM to T1-IFNs might explain why preclinical studies primarily show effects of T1-IFNs during acute TB when the GM-CSF/M-CSF ratio in the lungs is relatively low, but less pronounced effects during later stages when GM-CSF-levels progressively increase (see Section 2.4.3; FigURe 7 | The iL-17/type i interferons (T1-iFNs)/B-cell activating factor (BAFF) axis in tuberculosis (TB). Mtb actively induces NET Figure 3) (125). However, similar to IL-1β, prolonged GM-CSF formation by PMN, but subsequent activation of IFN-α production by signaling also appears detrimental in TB. In particular, GM-CSF plasmacytoid dendritic (pDC) appears less relevant in TB than in autoimmune contributes to foamy macrophage development during later diseases (AID). IL-17 levels from TB patients vary (Table 3), but preclinical stages of infection, which can sustain persistent mycobacteria models support a protective role. Dotted lines implicate mechanisms present and contribute to inflammation (125, 320). in AID that have not been confirmed in TB. Outstanding questions: (1) What are the specific contributions of IFN-α vs. IFN-β to disease in the different In summary, relatively few data are available on Th17.1 cells or phases of TB? (2) Do BAFF and T1-IFNs promote the observed autoimmune T-cell-derived GM-CSF in TB. The requirement for antigen stim- phenomena in TB? ulation of T-cells to induce expression of GM-CSF is interesting. Frontiers in Immunology | www.frontiersin.org 18 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB 5.2.1. PMN, NETs, and pDC in TB BOx 4 | iFN-α or iFN-β: which is relevant in tuberculosis (TB)? PMN isolated from SLE patients are the primary cells that IFN-α and IFN-β both exert their effect by binding to IFN-α/β receptor, but express the transcriptional T1-IFN signature. Furthermore, a increasing evidence from autoimmune diseases (AID) and viral infections sug- specific subclass of PMN, termed low-density granulocytes gests divergent effector functions (328, 329). In AID, this is illustrated by the (LDG) have been identified in SLE that express a pro- pathogenicity of IFN-α in systemic lupus erythematosus (SLE) opposed to the inflammatory phenotype, has increased T1-IFN-production therapeutic application of IFN-β as immunosuppressive treatment in multiple sclerosis (MS). Recently, these different immunoregulatory roles of IFN-α and and more readily form NETs than PMN from healthy indi- IFN-β in SLE and MS have been confirmed by more detailed analysis of blood viduals (291, 292). Similar to SLE, the transcriptional T1-IFN transcriptional profiles in patients (330). The molecular explanation for the signature in TB patients is mostly expressed in PMN (58). differential function of IFN-α and IFN-β traces back to subtle differences in Moreover, LDG are also present in TB patients and correlate receptor binding, signaling cascades, and feedback mechanisms initiated and with disease severity, but it is unclear if these cells also have a has been reviewed in detail elsewhere (28, 331). The specific contributions of IFN-α and IFN-β to the host response in infec- similarly increased tendency for NETosis as their SLE counter- tious disease have been studied particularly in mice infected with lymphocytic parts (321). Nevertheless, NETosis does occurs in TB, as Mtb choriomeningitis virus. This work supports an immune-stimulating, antiviral readily induces NETosis itself in PMN in an ESX-1-dependent role for IFN-α as opposed to an immunosuppressive effect by IFN-β (328, 331, way and can even stimulate extracellular trap formation in 332). IFN-β specifically inhibits antiviral T-cell responses and promotes viral persistence (331). In contrast, IFN-α-signaling associates with tissue damage macrophages (204, 322–324). and antiviral activity (331, 332). Neutrophil extracellular traps are strong inducers of IFN-α In TB, evidence for the involvement of both type I interferons is present. production in pDC in SLE (256). Conversely, pDC produce only Reactivation of TB has been reported specifically after treatment of patients small amounts of IFN-α and appear of minor clinical significance with IFN-α, but not IFN-β (50–57). Also, mice infected with virulent Mtb strains in TB (325). In accord, circulating pDC are elevated in SLE (326) specifically show higher IFN-α levels in the lungs compared to less virulent strains (64, 65). However, IFN-α-producing plasmacytoid dendritic cells seem but reduced in TB patients (327). to be of minor significance in TB patients (325, 327), and preclinical studies Final support for a limited role of pDC in TB pathogenesis show that Mtb preferentially induces IFN-β through cytoplasmic pattern comes from the observation that pDC produce IFN-α aer en ft do- recognition receptors and IRF3 instead of IFN-α through endosomal toll-like somal TLR-activation, while it is shown that Mtb primarily induces receptors and IRF7 (79–81). Mycobacterial persistence in patients with TB IFN-β through activation of cytoplasmic PRRs (see Section 2.3) is a major clinical problem and in line with the immunosuppressed state in active TB primarily supports a role for IFN-β (178, 333). However, exaggerated (81, 250). While both IFN-α and IFN-β signal through IFNAR, innate responses are also observed in TB where IFN-α might be involved. this diversification in cellular source and type of T1-IFN that is This is supported by recent evidence showing that IRF7 drives excessive induced can have important consequences for TB pathogenesis innate inflammation during bacterial infections and provides an interesting (see Box 4). therapeutic target (334). Taken together, little is known about the separate effects of IFN-α and IFN-β in TB, but clinical and preclinical studies support a role for both in different disease contexts. The diversification of IFN-α and 5.2.2. BAFF in TB IFN-β responses in transcriptional signatures observed in AID patients and the Both T1-IFNs and IL-17 can induce BAFF expression, which con- distinct effects of IFN-α and IFN-β in experimental LMCV infection therefore tributes to disease in SLE as illustrated by the clinical successes of provide highly interesting perspectives for TB. BAFF-inhibition (261, 271, 335). BAFF increases B-cell numbers and antibody titers (293, 336) and treatment with anti-BAFF in Additional support for a supposed protective role of BAFF in SLE patients reduces serum IgG levels (335). The role of BAFF in TB comes from its interaction with IL-17, which shows protective TB has been explored to a much lesser extent, with currently one effects in preclinical early infection phase TB models, as discussed paper demonstrating BAFF levels to be elevated in patients with active TB without elaborating on its functional contribution to in Section 3. IL-17 stimulates the migration of PMN to lymphoid structures where they can produce large quantities of BAFF that the host response (337). The functional role of BAFF in TB might be of particular directly drive plasma cell responses. Also, IL-17-induced G-CSF primes PMN for BAFF production upon activation (271, 294). interest given its stimulation of humoral immunity and the recently demonstrated protective effects of antibody-mediated Vice versa, elevated BAFF levels have been reported to increase Th17 immunity in AID and infection (268, 269, 343). immunity in TB patients (338, 339). Next to antibody-mediated protection, B-cells also essentially support T-cell responses in Taken together, preliminary pieces of evidence support the presence of interactions between IL-17, T1-IFNs, and BAFF in TB, but circulating B-cells are dysfunctional and reduced in absolute numbers in patients with active TB (340). The protec- TB, similar to those demonstrated in AID. This primarily includes the presence of NETs and elevated BAFF levels. However, despite tive effects of Mtb-specific antibodies and B cells in TB suggest that increased BAFF levels may supports host responses by the T1-IFN signature observed in TB, NET-induced IFN-α production by pDC appears less relevant in TB than in AID, and stimulating antibody production and perhaps other B cell func- tions such as stimulating T cell responses (338). However, high the specific contributions of IFN-α and IFN-β are of high inter - est in TB, but currently largely unknown. Studies in TB patients BAFF levels also predispose for the development of autoreactive B-cells in AID (341). Thus, elevated BAFF levels in TB could show protective effects of antibody-mediated immunity but also elevated titers of autoantibodies. This supports a view in which relate to the observation that up to 32% of patients with active TB have elevated autoantibody levels (12). Such correlations BAFF is protective in TB, but excessive BAFF levels, driven by either T1-IFNs or IL-17 can also increase the chances of develop- between elevated BAFF levels and autoimmunity have been demonstrated in other chronic infections (342). ing autoimmunity in TB patients. Frontiers in Immunology | www.frontiersin.org 19 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB Another interesting observation regarding T responses fh 5.3. TLS in TB concerns the induction of PD-L1 expression on APC and PD1 As a third place of interaction, IL-17, T1-IFNs, and BAFF converge on T-cells by T1-IFNs (43, 136, 307). In TB circulating PMN pri- in the local formation and functioning of TLS. In these structures, marily express the T1-IFN signature but also overexpress PD-L1 T cells support GC reactions in which B-cells differentiate into fh (58, 347). e in Th teraction of PD-L1 with PD1 on CD4 T-cells plasma cells and memory cells (295). As discussed in Section 4.3.4, is a key immunological checkpoint in TB that limits excessive observations in AID suggest that Th17 responses drive TLS devel- T-helper responses (33, 35). In line with this, PD1-deficient mice opment and facilitate an environment that promotes development are extraordinarily susceptible to TB (34). T cells constitutively fh of autoreactive B-cells under influence of T1-IFNs and BAFF. + + express PD1 , which distinguishes them from conventional CD4 Conversely, both TLS and Tfh cells are associated with immune T cells. Interestingly, while increased PD1/PD-L1 interaction control in TB patients and preclinical TB models, which is in line suppresses conventional T-helper responses, the opposite is with the protective role of humoral immunity in TB discussed in observed for T responses (348). Interaction between PD1 T fh fh the previous section (194, 201, 344, 345). Here, we discuss how cells with PD-L1 has a stronger suppressive effect on the regula- TLS and Tfh responses are associated with protective immunity in tory subset of T cells than on stimulatory T cells and results in fh fh TB and how interactions between IL-17, T1-IFNs, and BAFF may a net increase of T activity (348). fh contribute to this immune response. Taken together, IL-17, T1-IFNs, and BAFF act in concert to Migration of CXCR5 T cells into TLS is largely dependent on fh drive TLS formation and T responses. es Th e responses support fh CXCL13, which is primarily induced by IL-23 and IL-17 in mouse the development of autoreactive B-cells and the subsequent pro- TB models but can also be induced by T1-IFNs, as demonstrated duction of autoantibodies in AID but confer protective immunity in viral infections (194, 346). Mechanistically, CXCR5 Tfh cells in TB by improving the interaction between adaptive and innate mediate their protective effect in Mtb-infected mice by facilitat- cells and facilitating antibody production, while simultaneously ing optimal localization of effector T-cell populations within the inhibiting excessive inflammation by conventional CD4 T-cell lung parenchyma, thereby promoting efficient T-cell-dependent responses. macrophage activation and intracellular Mtb killing (194, 201). 6. CONCLUDiNg ReMARKS The notion that complex mechanisms beyond Th1 immunity are at play in TB immunity is supported by (1) the unsatis- factory results of vaccine strategies aimed at boosting Th1 immunity in TB patients (31); (2) the inflammatory damage associated with increasing IFN-γ production by T-cells in the lungs of Mtb-infected mice (33); and (3) the host-detrimental effect of targeting the Th1-inhibiting PD1/PD-L1 interaction in mice (34, 35). Patients with active TB express a T1-IFN transcriptional signature in their circulating leukocytes, but the exact identity and functional role of T1-IFNs in patients remains to be elu- cidated (62). Others have speculated that deleterious effects of T1-IFN-signaling during bacterial infections are tolerated because of their ability to suppress myeloid cell responses (41). This review highlights two additional aspects of T1-IFNs that are of interest in TB. The first concerns the preconditioning of myeloid cells prior to their contact with T1-IFNs. IFN-γ prim- ing appears essential for the induction of an Mtb-permissive phenotype, and monocytes that differentiate under GM-CSF are less responsive to T1-IFNs than their M-CSF-differentiated counterparts (Figure 3) (43, 94). The second aspect is the diver - sification of IFN-α and IFN-β responses on a transcriptional and functional level as explained in Box 4. We propose that the FigURe 8 | Tertiary lymphoid structures (TLS) in tuberculosis (TB). TLS, Tfh cells, B-cells, and antibodies are all associated with protective inflammatory effects of IRF7-mediated IFN-α might contribute immunity in TB. Preclinical TB models show that TLS induction and CXCL13 to excessive innate inflammatory responses in TB, while the production are driven by IL-17 and IL-23. Type I interferons (T1-IFNs) and immunosuppressive effects of IFN-β are more likely to support B-cell activating factor (BAFF) support TLS function and Tfh responses in mycobacterial persistence. autoimmune diseases (AID). In TB, T1-IFNs and BAFF are associated with active disease, but their functional role remains to be identified. Dotted lines Determination of the role of the Th17 response in TB is implicate mechanisms present in AID that have not been confirmed in TB. impeded by its heterogeneity, reflected in the presence of Outstanding question: (1) What are the functional roles of T1-IFNs and BAFF different Th17 subsets with ranging inflammatory potentials. in TLS function and humoral immunity in Mtb infection? Observations in AID emphasize the difference between IFN-γ/ Frontiers in Immunology | www.frontiersin.org 20 April 2017 | Volume 8 | Article 294 Mourik et al. Interactions between T1-IFNs and Th17 in TB GM-CSF-producing Th17.1 cells and regular IL-17-producing this manuscript for intellectual content, approved its final ver - Th17  cells. The exact role of T-cell-derived GM-CSF in TB sion for publication, and have agreed to be accountable for all remains to be determined, but preclinical TB studies show a pro- aspects of the work and in ensuring that questions related to the tective role for GM-CSF on monocyte differentiation in the acute accuracy or integrity of any part of the work are appropriately phase of TB. In contrast, IL-17 and PMN appear more relevant in investigated and resolved. chronic control of Mtb infection and recall immunity. Immunological similarities between TB and AID may result ACKNOwLeDgMeNTS from commonly activated pathogenic pathways. Alternatively, compensatory mechanisms induced by one disease might pre- e a Th uthors thank Ko Hagoort for his critical reading of the manuscript and Servier Medical Art (http://servier.com/ dispose for the development of the other. Interactions between IL-17, T1-IFNs, and BAFF form a pathological axis in AID that Powerpoint-image-bank) for providing base images for the figures. EL acknowledges the Dutch Arthritis Association promote autoantibody-mediated autoimmunity. e n Th ewly appreciated functional roles of antibodies, B-cells, (12-02-409; 13-3-403; 14-02-201; and 15-2-206). TO acknowl- cells in TB provide suggestive evidence that pathogenic edges EC FP7 ADITEC (Grant Agreement No. 280873); EC and Tfh mechanisms in AID confer protective immunity to TB. Further, HORIZON2020 TBVAC2020 (Grant Agreement No. 643381); insight into these mechanisms as discussed in Figures 6–8 may EC FP7 EURIPRED (FP7-INFRA-2012 Grant Agreement No. generate leads for immune-directed therapies adjunct to current 312661); The Netherlands Organization for Scientific Research and newly developed antimicrobial treatment protocols. (NWO-TOP Grant Agreement No. 91214038); The Bill & Melinda Gates Foundation Grand Challenges in Global Health (Grant GC6-2013); and the National Institute of Allergy and AUTHOR CONTRiBUTiONS Infectious Diseases of the National Institutes of Health under BM has written the manuscript and drafted the figures; EL Award Number R21AI127133. Research for this manuscript was has written the initial version of Section 4 and contributed (in part) performed within the framework of the Erasmus post- to the conception of Figure  5; JS and TO have contributed graduate school Molecular Medicine. The content is solely the substantially to Sections 1, 2, 3, and 5 and the conception of responsibility of the authors and does not necessarily represent Figures 1–3; PL has contributed substantially to the design of the official views of any funder. 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Interactions between T1-IFNs and Th17 in TB 346. Cohen KW, Dugast AS, Alter G, Mcelrath MJ, Stamatatos L. HIV-1 single- Conflict of Interest Statement: The authors declare that the research was con- stranded RNA induces CXCL13 secretion in human monocytes via TLR7 ducted in the absence of any commercial or financial relationships that could be activation and plasmacytoid dendritic cell-derived type I IFN. J Immunol construed as a potential conflict of interest. (2015) 194:2769–75. doi:10.4049/jimmunol.1400952 347. McNab FW, Berry MP, Graham CM, Bloch SA, Oni T, Wilkinson KA, Copyright © 2017 Mourik, Lubberts, de Steenwinkel, Ottenhoff and Leenen. i Th s is an et  al. Programmed death ligand 1 is over-expressed by neutrophils in the open-access article distributed under the terms of the Creative Commons Attribution blood of patients with active tuberculosis. Eur J Immunol (2011) 41:1941–7. License (CC BY). The use, distribution or reproduction in other forums is permit- doi:10.1002/eji.201141421 ted, provided the original author(s) or licensor are credited and that the original 348. Sage PT, Francisco LM, Carman CV, Sharpe AH. e r Th eceptor PD-1 controls publication in this journal is cited, in accordance with accepted academic practice. follicular regulatory T  cells in the lymph nodes and blood. Nat Immunol No use, distribution or reproduction is permitted which does not comply with these (2013) 14:152–61. doi:10.1038/ni.2496 terms. Frontiers in Immunology | www.frontiersin.org 31 April 2017 | Volume 8 | Article 294

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