Host immune responses to Toxoplasma gondii

Host immune responses to Toxoplasma gondii Abstract Toxoplasma gondii can infect homoeothermic animals including humans and cause lethal toxoplasmosis in immunocompromised individuals. When hosts are infected with T. gondii, the cells induce immune responses against T. gondii. The pathogen infection is recognized by immune sensors that directly detect T. gondii structural components, leading to production of pro-inflammatory cytokines and chemokines. Antigen-presenting cells such as macrophages and dendritic cells strongly activate T cells and induce development of Th1 cells and antigen-specific killer CD8 T cells. These T cells and Group 1 innate lymphoid cells are main producers of IFN-γ, which robustly stimulates cell-autonomous immunity in cells infected with T. gondii. IFN-γ-inducible effectors such as IFN-inducible GTPases, inducible nitric oxide synthase and indoleamine-2,3-dioxygenase differentially play important roles in suppression of T. gondii growth and its direct killing in anti-T. gondii cell-autonomous immune responses. In this review, we will describe our current knowledge of innate, adaptive and IFN-γ-mediated cell-autonomous immunity against T. gondii infection. acquired immunity, cell-autonomous immunity, IFN-inducible GTPases, innate immunity, IFN-γ Introduction Toxoplasma gondii is a protozoan parasite that infects nearly one-third of the world’s human population. Toxoplasma gondii infection in immunocompromised individuals such as those suffering from AIDS or those being treated with chemotherapy or immunosuppressive drugs can lead to symptomatic and often lethal toxoplasmosis (1). Toxoplasma gondii infection in pregnant women, if they are infected for the first time, can cause congenital diseases in fetuses and newborn children. Thus, T. gondii is an important pathogen of humans as well as animals. Toxoplasma gondii is an obligatory intracellular parasite that can infect virtually all nucleated cells of warm-blooded animals. Furthermore, T. gondii infection in healthy humans and animals becomes asymptomatic because host innate and adaptive immunity resists its initial proliferation and eradicates most of the parasites. Infection of monocytes by a T. gondii tachyzoite (a fast growing form of T. gondii) strongly induces innate immune responses such as the production of pro-inflammatory cytokines, resulting in the activation of adaptive immune responses mediated by T and B cells. The activation of adaptive immunity further stimulates cell-autonomous immune responses in infected cells to disrupt intracellular growth of the protozoa and mediate its clearance, inducing T. gondii stage conversion into a bradyzoite (a form that grows slowly but evades host immune responses) that eventually leads to chronic infection. Thus, the immunological balance between a healthy host and T. gondii is a key step in T. gondii immunobiology. In this review, we will summarize previous and current studies of anti-T. gondii innate, adaptive and cell-autonomous immune responses. Primary immune responses against T. gondii infection Innate immunity is the first line of host defense against pathogen infection. Infected hosts need to detect the invasion of pathogens to prevent their spread. TLRs recognize microbial components termed pathogen-associated molecular patterns (PAMPs). TLRs consist of 13 family members in mice and each TLR recognizes different ligands and induces the production of various cytokines and chemokines (1–3). Toxoplasma gondii-induced IL-12 production in dendritic cells (DCs) was dramatically decreased in mice lacking MyD88, an adaptor molecule in TLR signaling pathways, or in mice lacking CCR5 (4, 5). Stimulation with cyclophilin-18 from T. gondii induced the expression of CCR5 in DCs (5). Profilin-like protein, which is not required for the intracellular growth of T. gondii, but is indispensable for invasion, host cell invasion and active egress from cells (6), was identified as a ligand of TLR11 (7). Both ligands stimulated IL-12 production in CD8α+ DCs and CD8α– DCs. In addition to TLR11, TLR12 recognizes profilin-like protein and is critical for IL-12 production, especially in plasmacytoid DCs (pDCs) (8). Although humans do not express either TLR11 or TLR12, human monocytes produce pro-inflammatory cytokines in response to T. gondii infection, suggesting that other TLRs in humans recognize different compartments of T. gondii to produce IL-12 in antigen-presenting cells. TLR11 and TLR12 form heterodimers or homodimers with each other and with endosomal TLRs such as TLR3, TLR7 and TLR9. TLR7 and TLR9 recognize RNA and DNA derived from T. gondii, respectively (9). It is also possible that nucleic acid recognition by endosomal TLRs (including TLR8 in humans) warns of parasite infection and induces IL-12 production in human cells. A second possibility is the presence of an unidentified sensor(s) that recognizes T. gondii infection in humans, independent of TLRs and CCR5. Further investigations are required to identify this sensor. The most common route of T. gondii infection is through the oral ingestion of T. gondii cysts in undercooked meat and/or dirty water. The intestine is a primary site of T. gondii infection after the oral ingestion of a cyst. Innate lymphoid cells (ILCs) are a newly identified lymphocyte subset that is related to innate immunity. ILCs are classified into three groups (10): Group 1 ILCs (ILC1s) consist of ILC1s and conventional NK (cNK) cells, which produce Th1 cytokines including IFN-γ and TNF-α (11); Group 2 ILCs produce Th2 cytokines such as IL-4, IL-5, IL-9 and IL-13; and Group 3 ILCs (ILC3s) produce IL-17A and IL-22 and also specifically express a transcriptional factor RORγt (12). ILC1s mainly produce IFN-γ and TNF-α in the small intestine in response to oral infection by T. gondii (13). However, Ahr-deficient mice, in which ILC3s are present in lower numbers in the lamina propria compared with wild-type mice, exhibit hyperactivation of CD4 T cells in response to T. gondii infection, indicating that ILC3s indirectly regulate immune responses to T. gondii infection (14). Interestingly, the mechanism of how ILCs are stimulated by T. gondii infection to produce cytokines is unclear. In addition, the role of ILCs in parasite-specific antibody generation also remains to be determined (Fig. 1). Fig. 1. View largeDownload slide Recognition of T. gondii by innate immune cells leads to activation of acquired immunity. Macrophages and DCs produce various inflammatory cytokines and chemokines to promote IFN-γ production from T cells, NK cells or ILC1 and recruitment of neutrophils and inflammatory monocytes to the infected sites. Fig. 1. View largeDownload slide Recognition of T. gondii by innate immune cells leads to activation of acquired immunity. Macrophages and DCs produce various inflammatory cytokines and chemokines to promote IFN-γ production from T cells, NK cells or ILC1 and recruitment of neutrophils and inflammatory monocytes to the infected sites. Secondary immune responses against T. gondii infection Many cytokines are induced by T. gondii infection (15). Activated macrophages produce IL-1β and TNF-α (16, 17). It was reported that exogenous treatment with IL-1α or IL-1β with TNF-α promoted protection against T. gondii infection in vivo (18). IL-12, TNF-α and IFN-γ are important cytokines produced after T. gondii infection (19, 20). IL-12 production from conventional DCs, macrophages and pDCs triggers the proliferation of NK cells, CD4 T cells and CD8 T cells, which mediate cytotoxicity and the production of high amounts of IFN-γ (21, 22). Treatment of T. gondii-infected SCID mice (which lack B and T lymphocytes) with recombinant IL-12 induced IFN-γ and decreased their mortality, suggesting that IFN-γ production from NK cells is critical for survival in the acute phase of T. gondii infection in vivo. However, common cytokine receptor γ-chain (γc)-deficient mice, which lack NK cells and CD8 T cells, are not susceptible to T. gondii infection at the acute phase (23). The depletion of T cells or NK cells did not affect the survival rate at the acute phase of T. gondii infection (23), indicating that IFN-γ production from CD4 T cells or NK cells is sufficient for control of the acute stage of T. gondii infection. IFN-γ production during T. gondii infection is regulated by at least three different cell types (NK cells, ILC1s and T cells) and these cells may compensate for each other. Inducible nitric oxide synthase (iNOS) is expressed upon T. gondii infection because it is an IFN-γ inducible gene. Mice deficient for iNOS are normal at the acute phase of infection, but show increased lethality during parasite expansion and severe pathology caused by the increased parasite burden in the brain (24, 25). NO, produced via iNOS activation, prevents the fatal exacerbation of progressive toxoplasmic encephalitis (TE). Interestingly, the effect of iNOS is only critical in C57BL/6 mice, but not in BALB/c mice, because fatal TE never occurs in BALB/c mice (26). IFN-γ stimulates the robust expression of indoleamine 2,3-dioxygenase (IDO), which mediates tryptophan degradation to inhibit the growth of T. gondii in several human cell lines including fibroblasts, glioblastoma cells, retinal pigment epithelial cells and macrophages (16, 27–30). In addition to IL-12-producing cells such as DCs and macrophages, various other cell types are involved in T. gondii infection. Neutrophils and inflammatory monocytes are important cells that prevent T. gondii infection (24). When animals are infected with T. gondii, primary infected cells include intestinal epithelial cells or peritoneal cells under natural or experimental conditions. Antigen-presenting cells such as DCs and macrophages recognize parasite components including virulence factors and induce the expression of genes encoding chemokines such as CCL2 and CXCL2 (31, 32). These chemokines induce the migration of Ly6ChighCCR2+ monocytes and neutrophils to the infection site (33). Although these leukocytes spread infectious parasites, the infection is still controllable if IFN-γ and IFN-inducible genes are adequately expressed (34). However, there is another feature of Ly6ChighCCR2+ monocytes. These cells produce IL-10, a regulatory cytokine that prevents toxoplasmosis in the brain (35), indicating that Ly6ChighCCR2+ monocytes have a dual impact on T. gondii infection (35) (Fig. 1). Although the immune system is usually suppressed by IL-10-producing CD4 T cells, which also express FoxP3, to maintain homeostasis, these cells should be activated once infection occurs. The number of Foxp3+ T cells was reduced during T. gondii infection because of decreased IL-2 concentrations at the infection site, which are required for the induction of Th1 immune responses (e.g. IFN-γ) against T. gondii (36). However, immune suppression following activation is also an important step to prevent immunopathology during T. gondii infection. IL-10 and IL-22 are members of the IL-10 cytokine family that have anti-inflammatory effects (37). IL-10 production was induced at early (38) and clinical phases of T. gondii infection, especially in the brain (39), and IL-12 production was inhibited by enhancing the production of Th2 cytokines such as IL-4 and IL-10. Mice deficient in IL-10 or treated with anti-IL-10 neutralizing antibodies are susceptible because of excessive inflammation (40–42). IL-10-producing cells induced by T. gondii infection include regulatory B cells and T-bet+Foxp3– Th1 cells (43, 44). IL-10-producing T-bet+Foxp3– Th1 cells also secrete IFN-γ (44). IFN-γ signaling also induces the Th1 transcription factor T-bet on Foxp3+ T cells, and T-bet in turn promotes the expression of CXCR3 (45). T-bet+CXCR3+ Treg cells also express IL-27 during T. gondii infection, which promotes the suppression of Th1 Treg cells through IL-10 production (46). IL-33 amplifies Th2 responses and reduces Th1 responses. IL-33 signaling regulated toxoplasmosis in the brain and eyes (47, 48). Further investigations are required to determine the importance of IL-33 signaling during T. gondii infection. Cell-autonomous immune responses against T. gondii infection Recently, one of the hot topics in host defense against T. gondii infection has been the analysis of IFN-γ-induced effector mechanisms. Most cells respond to IFN-γ stimulation by expressing several hundred genes, including four families of GTPases: MX proteins, p47 immunity-related GTPases (IRGs), VLIGs and p65 guanylate-binding proteins (GBPs) (49). IRGs and GBPs are important for IFN-γ-induced anti-T. gondii responses. IRGs are a group of 47–48 kDa proteins and consist of Irgm3 (also known as IGTP) (50), Irgm1 (LRG-47) (51), Irgd (IRG47) (52), Irgb6 (TGTP) (53, 54), Irga6 (IIGP1) and Irgm2 (GTPI) (55). All IRGs have a GTP-binding domain and are classified into two subgroups: GKS-IRG and GMS-IRG (55, 56). GMS-IRG consists of Irgm1, Irgm2 and Irgm3 in mice and the cellular localization of these molecules is mainly at the endoplasmic reticulum and Golgi (57–59). Except for GMS-IRG, all IRGs belong to GKS-IRGs, among which Irga6 and Irgb6 play major roles in anti-T. gondii responses (56). The mechanism of how GMS-IRG affects GKS-IRG is unclear. A previous report suggested that GMS-IRG forms a heterodimer with GKS-IRG to inhibit its activation (60). Irgm1- or Irgm3-deficient mice and mice doubly deficient for Irgm1 and Irgm3 are highly susceptible to T. gondii infection because the expression levels of Irga6 and Irgb6 are reduced and because the localization of Irga6 and Irgb6 is altered in infected cells (61, 62). The parasitophorous vacuole (PV) is a specialized compartment generated by T. gondii in infected cells. Toxoplasma gondii multiplies within this vacuole until the host cells releases T. gondii particles into the extracellular space to infect further cells. The effects of most IRGs on T. gondii are mediated by the recruitment of the T. gondii parasitophorous vacuole membrane (PVM) (63–65). Irga6 and Irgb6 accumulate around the PVM and disrupt it (60, 66). GBPs consist of 7 and 11 family members in humans and mice, respectively. GBP genes are aligned in two clusters located on chromosome 3 and chromosome 5 in mice. GBP1 and 7 have been reported to function in host defense against Listeria monocytogenes, Mycobacterium bovis BCG and T. gondii infection (67, 68). Mice lacking GBPs on chromosome 3 (GBPchr3), including GBP1, GBP2, GBP3, GBP5 and GBP7, have a high susceptibility to T. gondii infection because of the defective disruption of the PVM (69). In addition, macrophages lacking GBPchr3 show defective Irgb6 loading on T. gondii PVM (69). In contrast, GBP1- or GBP2-deficient mice exhibited a milder reduction of survival rates compared with GBPchr3 deficient mice, suggesting that each GBP on chromosome 3 has complementary or individual roles in host defense against T. gondii infection (68, 70) (Fig. 2). Fig. 2. View largeDownload slide IFN-γ-induced cell-autonomous immunity to T. gondii. IFN-γ stimulates robust expression of IFN-inducible proteins including IFN-inducible GTPases (IRGs and GBPs). GBPs are localized in Gate-16 vesicles, which are generated dependently on some autophagy-regulated proteins. Fig. 2. View largeDownload slide IFN-γ-induced cell-autonomous immunity to T. gondii. IFN-γ stimulates robust expression of IFN-inducible proteins including IFN-inducible GTPases (IRGs and GBPs). GBPs are localized in Gate-16 vesicles, which are generated dependently on some autophagy-regulated proteins. The roles of ubiquitination and of autophagy-regulated proteins in responses against T. gondii infection The molecular mechanisms of how GTPases localize and recognize the PVM remain an open question. Experiments using chimeric mutants of GBP2 and GBP5 indicated that the C-terminal isoprenylation of GBP2 regulated the recruitment of GBP2 to the PVM. However, isoprenylation alone cannot distinguish membranes of host organelles from PVs. Ubiquitination on the PVM does, however, discriminate between the host membrane and the PVM, since ubiquitin recognition on intracellular bacteria triggers critical host effector mechanisms (71, 72). The types of ubiquitination on the T. gondii PVM have been identified as M1 linear, K48 and K63-linked polyubiquitin chains (73–75). TRAF6 and TRIM21 regulate ubiquitination on the T. gondii PVM following IFN-γ treatment. However, the effect of TRAF6 on the IFN-γ-induced clearance of T. gondii is controversial (73, 74). Disruption of the PVM as well as the accumulation of ubiquitin on PVM were largely intact in TRIM21-deficient cells, suggesting that other E3 ligases such as TRAF6 may compensate ubiquitination on the T. gondii PVM (76). Analysis of cells doubly deficient for TRAF6 and TRIM21 might reveal these compensatory roles or, if they still show ubiquitination, they might suggest the participation of other E3 ligases in the IFN-γ-induced ubiquitination of the T. gondii PVM. As well as the role of ubiquitin in the recruitment of GBPs and IRGs to the PVM being in dispute, the biological significance of the recruitment of ubiquitin-binding effector p62/Sqstm1 is also controversial. One study showed that p62 plays a role in IFN-γ-mediated T. gondii clearance (74). On the other hand, another study demonstrated that p62 was not important in parasite clearance but was involved in presenting vacuolar antigens to CD8 T cells (73). Autophagy is another process that can discriminate between host membranes and T. gondii PVM. Autophagy is a self-degradative process that, for example, regenerates energy during embryonic development and in response to nutrient stress (77). Autophagy is tightly controlled by autophagy-regulated (ATG) genes (77). ATG8 is a ubiquitin-like protein required for the formation of autophagosomal membrane in yeast (78). Mammalian Atg8 consists of the LC3 subfamily such as LC3A and LC3B in addition to LC3C in humans and the GABARAP subfamily such as Gabarap, Gabarapl1 and Gate-16/Gabarapl2 (79). LC3B is a homologue of yeast Atg8 in mammals and accumulates on autophagosomes to remove intracellular pathogens from cells. Eventually, LC3-coated autophagosomes fuse with lysosomes (80). The autophagic process against pathogens is called xenophagy (81). LC3 also accumulates on the T. gondii PVM when cells are activated via CD40. CD40 stimulation might induce the activation of phosphoinositide-3-class 3 (PIK3C3), Rab7 and vacuolar ATPase to fuse PVM with late endosomes or lysosomes (82). However, LC3 recruitment to the T. gondii PV in response to IFN-γ treatment is controversial (34, 66, 83, 84) and it might be possible that autophagy is not functionally involved in anti-parasite immune responses mediated by IFN-γ. In autophagy, Atg12 and Atg5 form a complex that induces the conjugation of phosphatidylethanolamine (PE) on Atg8 (85). Cells lacking Atg5, an essential autophagy-related molecule, showed a defect in IFN-γ-mediated PV disruption, which is critical to prevent T. gondii replication (83). Because T. gondii PV or degraded parasites were not enveloped by double membranes, a hallmark of autophagy, the role of Atg5 in the IFN-γ-mediated anti-T. gondii response is independent of autophagy (86). Atg family members that belong to the Atg12 conjugation system, such as Atg3, Atg7 and Atg16L1, also participate in IFN-γ-mediated anti-T. gondii responses, but other Atg proteins that regulate the pathway containing ULK1, PI3K and Atg9 do not. Therefore, IFN-γ-mediated anti-T. gondii responses can be regulated by these Atg proteins in an autophagy-independent manner (72, 87, 88). Recently, we reported that a GABARAP subfamily member in the Atg8 family critically regulated the uniform cytosolic localization of GBPs, facilitating the efficient clearance of T. gondii. GBPs are localized at cytoplasmic vesicular-like structures and are equally distributed in IFN-γ-stimulated cells (68). Among GABARAP subfamily members, Gate-16 is the most important for GBP distribution, and its expression in LysM+ myeloid cells, mainly macrophages, neutrophils and monocytes, is essential for the survival of mice during the acute phase of T. gondii infection (34). Thus, the distribution of GBPs in the cytosol triggers the disruption of the PVM and is tightly regulated by autophagy proteins in an autophagy-independent fashion (Fig. 2). Conclusion Analysis of innate and adaptive immune responses to T. gondii has been extensively performed in mice and has elucidated various fundamental processes that have contributed to conceptual advances in immunology. Recent progress on cell-autonomous host defense has suggested there are still unidentified biological processes in anti-T. gondii immunity. Cell-autonomous immunity mediated by IFN-inducible GTPases such as GBPs and IRGs is important for anti-T. gondii responses as well as anti-bacterial immunity, where bacteria-containing vacuoles are disrupted by GBPs and IRGs in a similar fashion to T. gondii PVs (84, 89–91). This suggests a universal role for IFN-inducible GTPases in cell-autonomous immunity against vacuole-forming pathogens. In addition, the analysis of anti-T. gondii has revealed novel aspects of ILCs. Moreover, T. gondii secretes various virulence factors that suppress host immune responses (92, 93). The analysis of host factors targeted by virulence factors may reveal an unexpected immunological function of these factors or links between immunology and other fundamental biological fields. Thus, T. gondii will be a useful tool for immunological studies in the future. Funding Our work was supported by the Research Program on Emerging and Re-emerging Infectious Diseases (17fk0108120h0001) and the Japanese Initiative for Progress of Research on Infectious Diseases for Global Epidemics (17fm0208018h0001) from the Agency for Medical Research and Development (AMED), a Grant-in-Aid for Scientific Research on Innovative Areas (17K15677) from the Ministry of Education, Culture, Sports, Science and Technology, a Cooperative Research Grant of the Institute for Enzyme Research, Joint Usage/Research Center, Tokushima University, the Takeda Science Foundation, the Ohyama Health Foundation, the Heiwa Nakajima Foundation, the Cell Science Research Foundation, the Mochida Memorial Foundation on Medical and Pharmaceutical Research, the Senri Life Science Research Foundation and the Research Foundation for Microbial Diseases of Osaka University. Acknowledgement We thank M. Enomoto for secretarial and technical assistance. 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Toxoplasma’s ways of manipulating the host transcriptome via secreted effectors. Curr. Opin. Microbiol . 26: 24. Google Scholar CrossRef Search ADS PubMed  © The Japanese Society for Immunology. 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Immunology Oxford University Press

Host immune responses to Toxoplasma gondii

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© The Japanese Society for Immunology. 2018. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com
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0953-8178
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10.1093/intimm/dxy004
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Abstract

Abstract Toxoplasma gondii can infect homoeothermic animals including humans and cause lethal toxoplasmosis in immunocompromised individuals. When hosts are infected with T. gondii, the cells induce immune responses against T. gondii. The pathogen infection is recognized by immune sensors that directly detect T. gondii structural components, leading to production of pro-inflammatory cytokines and chemokines. Antigen-presenting cells such as macrophages and dendritic cells strongly activate T cells and induce development of Th1 cells and antigen-specific killer CD8 T cells. These T cells and Group 1 innate lymphoid cells are main producers of IFN-γ, which robustly stimulates cell-autonomous immunity in cells infected with T. gondii. IFN-γ-inducible effectors such as IFN-inducible GTPases, inducible nitric oxide synthase and indoleamine-2,3-dioxygenase differentially play important roles in suppression of T. gondii growth and its direct killing in anti-T. gondii cell-autonomous immune responses. In this review, we will describe our current knowledge of innate, adaptive and IFN-γ-mediated cell-autonomous immunity against T. gondii infection. acquired immunity, cell-autonomous immunity, IFN-inducible GTPases, innate immunity, IFN-γ Introduction Toxoplasma gondii is a protozoan parasite that infects nearly one-third of the world’s human population. Toxoplasma gondii infection in immunocompromised individuals such as those suffering from AIDS or those being treated with chemotherapy or immunosuppressive drugs can lead to symptomatic and often lethal toxoplasmosis (1). Toxoplasma gondii infection in pregnant women, if they are infected for the first time, can cause congenital diseases in fetuses and newborn children. Thus, T. gondii is an important pathogen of humans as well as animals. Toxoplasma gondii is an obligatory intracellular parasite that can infect virtually all nucleated cells of warm-blooded animals. Furthermore, T. gondii infection in healthy humans and animals becomes asymptomatic because host innate and adaptive immunity resists its initial proliferation and eradicates most of the parasites. Infection of monocytes by a T. gondii tachyzoite (a fast growing form of T. gondii) strongly induces innate immune responses such as the production of pro-inflammatory cytokines, resulting in the activation of adaptive immune responses mediated by T and B cells. The activation of adaptive immunity further stimulates cell-autonomous immune responses in infected cells to disrupt intracellular growth of the protozoa and mediate its clearance, inducing T. gondii stage conversion into a bradyzoite (a form that grows slowly but evades host immune responses) that eventually leads to chronic infection. Thus, the immunological balance between a healthy host and T. gondii is a key step in T. gondii immunobiology. In this review, we will summarize previous and current studies of anti-T. gondii innate, adaptive and cell-autonomous immune responses. Primary immune responses against T. gondii infection Innate immunity is the first line of host defense against pathogen infection. Infected hosts need to detect the invasion of pathogens to prevent their spread. TLRs recognize microbial components termed pathogen-associated molecular patterns (PAMPs). TLRs consist of 13 family members in mice and each TLR recognizes different ligands and induces the production of various cytokines and chemokines (1–3). Toxoplasma gondii-induced IL-12 production in dendritic cells (DCs) was dramatically decreased in mice lacking MyD88, an adaptor molecule in TLR signaling pathways, or in mice lacking CCR5 (4, 5). Stimulation with cyclophilin-18 from T. gondii induced the expression of CCR5 in DCs (5). Profilin-like protein, which is not required for the intracellular growth of T. gondii, but is indispensable for invasion, host cell invasion and active egress from cells (6), was identified as a ligand of TLR11 (7). Both ligands stimulated IL-12 production in CD8α+ DCs and CD8α– DCs. In addition to TLR11, TLR12 recognizes profilin-like protein and is critical for IL-12 production, especially in plasmacytoid DCs (pDCs) (8). Although humans do not express either TLR11 or TLR12, human monocytes produce pro-inflammatory cytokines in response to T. gondii infection, suggesting that other TLRs in humans recognize different compartments of T. gondii to produce IL-12 in antigen-presenting cells. TLR11 and TLR12 form heterodimers or homodimers with each other and with endosomal TLRs such as TLR3, TLR7 and TLR9. TLR7 and TLR9 recognize RNA and DNA derived from T. gondii, respectively (9). It is also possible that nucleic acid recognition by endosomal TLRs (including TLR8 in humans) warns of parasite infection and induces IL-12 production in human cells. A second possibility is the presence of an unidentified sensor(s) that recognizes T. gondii infection in humans, independent of TLRs and CCR5. Further investigations are required to identify this sensor. The most common route of T. gondii infection is through the oral ingestion of T. gondii cysts in undercooked meat and/or dirty water. The intestine is a primary site of T. gondii infection after the oral ingestion of a cyst. Innate lymphoid cells (ILCs) are a newly identified lymphocyte subset that is related to innate immunity. ILCs are classified into three groups (10): Group 1 ILCs (ILC1s) consist of ILC1s and conventional NK (cNK) cells, which produce Th1 cytokines including IFN-γ and TNF-α (11); Group 2 ILCs produce Th2 cytokines such as IL-4, IL-5, IL-9 and IL-13; and Group 3 ILCs (ILC3s) produce IL-17A and IL-22 and also specifically express a transcriptional factor RORγt (12). ILC1s mainly produce IFN-γ and TNF-α in the small intestine in response to oral infection by T. gondii (13). However, Ahr-deficient mice, in which ILC3s are present in lower numbers in the lamina propria compared with wild-type mice, exhibit hyperactivation of CD4 T cells in response to T. gondii infection, indicating that ILC3s indirectly regulate immune responses to T. gondii infection (14). Interestingly, the mechanism of how ILCs are stimulated by T. gondii infection to produce cytokines is unclear. In addition, the role of ILCs in parasite-specific antibody generation also remains to be determined (Fig. 1). Fig. 1. View largeDownload slide Recognition of T. gondii by innate immune cells leads to activation of acquired immunity. Macrophages and DCs produce various inflammatory cytokines and chemokines to promote IFN-γ production from T cells, NK cells or ILC1 and recruitment of neutrophils and inflammatory monocytes to the infected sites. Fig. 1. View largeDownload slide Recognition of T. gondii by innate immune cells leads to activation of acquired immunity. Macrophages and DCs produce various inflammatory cytokines and chemokines to promote IFN-γ production from T cells, NK cells or ILC1 and recruitment of neutrophils and inflammatory monocytes to the infected sites. Secondary immune responses against T. gondii infection Many cytokines are induced by T. gondii infection (15). Activated macrophages produce IL-1β and TNF-α (16, 17). It was reported that exogenous treatment with IL-1α or IL-1β with TNF-α promoted protection against T. gondii infection in vivo (18). IL-12, TNF-α and IFN-γ are important cytokines produced after T. gondii infection (19, 20). IL-12 production from conventional DCs, macrophages and pDCs triggers the proliferation of NK cells, CD4 T cells and CD8 T cells, which mediate cytotoxicity and the production of high amounts of IFN-γ (21, 22). Treatment of T. gondii-infected SCID mice (which lack B and T lymphocytes) with recombinant IL-12 induced IFN-γ and decreased their mortality, suggesting that IFN-γ production from NK cells is critical for survival in the acute phase of T. gondii infection in vivo. However, common cytokine receptor γ-chain (γc)-deficient mice, which lack NK cells and CD8 T cells, are not susceptible to T. gondii infection at the acute phase (23). The depletion of T cells or NK cells did not affect the survival rate at the acute phase of T. gondii infection (23), indicating that IFN-γ production from CD4 T cells or NK cells is sufficient for control of the acute stage of T. gondii infection. IFN-γ production during T. gondii infection is regulated by at least three different cell types (NK cells, ILC1s and T cells) and these cells may compensate for each other. Inducible nitric oxide synthase (iNOS) is expressed upon T. gondii infection because it is an IFN-γ inducible gene. Mice deficient for iNOS are normal at the acute phase of infection, but show increased lethality during parasite expansion and severe pathology caused by the increased parasite burden in the brain (24, 25). NO, produced via iNOS activation, prevents the fatal exacerbation of progressive toxoplasmic encephalitis (TE). Interestingly, the effect of iNOS is only critical in C57BL/6 mice, but not in BALB/c mice, because fatal TE never occurs in BALB/c mice (26). IFN-γ stimulates the robust expression of indoleamine 2,3-dioxygenase (IDO), which mediates tryptophan degradation to inhibit the growth of T. gondii in several human cell lines including fibroblasts, glioblastoma cells, retinal pigment epithelial cells and macrophages (16, 27–30). In addition to IL-12-producing cells such as DCs and macrophages, various other cell types are involved in T. gondii infection. Neutrophils and inflammatory monocytes are important cells that prevent T. gondii infection (24). When animals are infected with T. gondii, primary infected cells include intestinal epithelial cells or peritoneal cells under natural or experimental conditions. Antigen-presenting cells such as DCs and macrophages recognize parasite components including virulence factors and induce the expression of genes encoding chemokines such as CCL2 and CXCL2 (31, 32). These chemokines induce the migration of Ly6ChighCCR2+ monocytes and neutrophils to the infection site (33). Although these leukocytes spread infectious parasites, the infection is still controllable if IFN-γ and IFN-inducible genes are adequately expressed (34). However, there is another feature of Ly6ChighCCR2+ monocytes. These cells produce IL-10, a regulatory cytokine that prevents toxoplasmosis in the brain (35), indicating that Ly6ChighCCR2+ monocytes have a dual impact on T. gondii infection (35) (Fig. 1). Although the immune system is usually suppressed by IL-10-producing CD4 T cells, which also express FoxP3, to maintain homeostasis, these cells should be activated once infection occurs. The number of Foxp3+ T cells was reduced during T. gondii infection because of decreased IL-2 concentrations at the infection site, which are required for the induction of Th1 immune responses (e.g. IFN-γ) against T. gondii (36). However, immune suppression following activation is also an important step to prevent immunopathology during T. gondii infection. IL-10 and IL-22 are members of the IL-10 cytokine family that have anti-inflammatory effects (37). IL-10 production was induced at early (38) and clinical phases of T. gondii infection, especially in the brain (39), and IL-12 production was inhibited by enhancing the production of Th2 cytokines such as IL-4 and IL-10. Mice deficient in IL-10 or treated with anti-IL-10 neutralizing antibodies are susceptible because of excessive inflammation (40–42). IL-10-producing cells induced by T. gondii infection include regulatory B cells and T-bet+Foxp3– Th1 cells (43, 44). IL-10-producing T-bet+Foxp3– Th1 cells also secrete IFN-γ (44). IFN-γ signaling also induces the Th1 transcription factor T-bet on Foxp3+ T cells, and T-bet in turn promotes the expression of CXCR3 (45). T-bet+CXCR3+ Treg cells also express IL-27 during T. gondii infection, which promotes the suppression of Th1 Treg cells through IL-10 production (46). IL-33 amplifies Th2 responses and reduces Th1 responses. IL-33 signaling regulated toxoplasmosis in the brain and eyes (47, 48). Further investigations are required to determine the importance of IL-33 signaling during T. gondii infection. Cell-autonomous immune responses against T. gondii infection Recently, one of the hot topics in host defense against T. gondii infection has been the analysis of IFN-γ-induced effector mechanisms. Most cells respond to IFN-γ stimulation by expressing several hundred genes, including four families of GTPases: MX proteins, p47 immunity-related GTPases (IRGs), VLIGs and p65 guanylate-binding proteins (GBPs) (49). IRGs and GBPs are important for IFN-γ-induced anti-T. gondii responses. IRGs are a group of 47–48 kDa proteins and consist of Irgm3 (also known as IGTP) (50), Irgm1 (LRG-47) (51), Irgd (IRG47) (52), Irgb6 (TGTP) (53, 54), Irga6 (IIGP1) and Irgm2 (GTPI) (55). All IRGs have a GTP-binding domain and are classified into two subgroups: GKS-IRG and GMS-IRG (55, 56). GMS-IRG consists of Irgm1, Irgm2 and Irgm3 in mice and the cellular localization of these molecules is mainly at the endoplasmic reticulum and Golgi (57–59). Except for GMS-IRG, all IRGs belong to GKS-IRGs, among which Irga6 and Irgb6 play major roles in anti-T. gondii responses (56). The mechanism of how GMS-IRG affects GKS-IRG is unclear. A previous report suggested that GMS-IRG forms a heterodimer with GKS-IRG to inhibit its activation (60). Irgm1- or Irgm3-deficient mice and mice doubly deficient for Irgm1 and Irgm3 are highly susceptible to T. gondii infection because the expression levels of Irga6 and Irgb6 are reduced and because the localization of Irga6 and Irgb6 is altered in infected cells (61, 62). The parasitophorous vacuole (PV) is a specialized compartment generated by T. gondii in infected cells. Toxoplasma gondii multiplies within this vacuole until the host cells releases T. gondii particles into the extracellular space to infect further cells. The effects of most IRGs on T. gondii are mediated by the recruitment of the T. gondii parasitophorous vacuole membrane (PVM) (63–65). Irga6 and Irgb6 accumulate around the PVM and disrupt it (60, 66). GBPs consist of 7 and 11 family members in humans and mice, respectively. GBP genes are aligned in two clusters located on chromosome 3 and chromosome 5 in mice. GBP1 and 7 have been reported to function in host defense against Listeria monocytogenes, Mycobacterium bovis BCG and T. gondii infection (67, 68). Mice lacking GBPs on chromosome 3 (GBPchr3), including GBP1, GBP2, GBP3, GBP5 and GBP7, have a high susceptibility to T. gondii infection because of the defective disruption of the PVM (69). In addition, macrophages lacking GBPchr3 show defective Irgb6 loading on T. gondii PVM (69). In contrast, GBP1- or GBP2-deficient mice exhibited a milder reduction of survival rates compared with GBPchr3 deficient mice, suggesting that each GBP on chromosome 3 has complementary or individual roles in host defense against T. gondii infection (68, 70) (Fig. 2). Fig. 2. View largeDownload slide IFN-γ-induced cell-autonomous immunity to T. gondii. IFN-γ stimulates robust expression of IFN-inducible proteins including IFN-inducible GTPases (IRGs and GBPs). GBPs are localized in Gate-16 vesicles, which are generated dependently on some autophagy-regulated proteins. Fig. 2. View largeDownload slide IFN-γ-induced cell-autonomous immunity to T. gondii. IFN-γ stimulates robust expression of IFN-inducible proteins including IFN-inducible GTPases (IRGs and GBPs). GBPs are localized in Gate-16 vesicles, which are generated dependently on some autophagy-regulated proteins. The roles of ubiquitination and of autophagy-regulated proteins in responses against T. gondii infection The molecular mechanisms of how GTPases localize and recognize the PVM remain an open question. Experiments using chimeric mutants of GBP2 and GBP5 indicated that the C-terminal isoprenylation of GBP2 regulated the recruitment of GBP2 to the PVM. However, isoprenylation alone cannot distinguish membranes of host organelles from PVs. Ubiquitination on the PVM does, however, discriminate between the host membrane and the PVM, since ubiquitin recognition on intracellular bacteria triggers critical host effector mechanisms (71, 72). The types of ubiquitination on the T. gondii PVM have been identified as M1 linear, K48 and K63-linked polyubiquitin chains (73–75). TRAF6 and TRIM21 regulate ubiquitination on the T. gondii PVM following IFN-γ treatment. However, the effect of TRAF6 on the IFN-γ-induced clearance of T. gondii is controversial (73, 74). Disruption of the PVM as well as the accumulation of ubiquitin on PVM were largely intact in TRIM21-deficient cells, suggesting that other E3 ligases such as TRAF6 may compensate ubiquitination on the T. gondii PVM (76). Analysis of cells doubly deficient for TRAF6 and TRIM21 might reveal these compensatory roles or, if they still show ubiquitination, they might suggest the participation of other E3 ligases in the IFN-γ-induced ubiquitination of the T. gondii PVM. As well as the role of ubiquitin in the recruitment of GBPs and IRGs to the PVM being in dispute, the biological significance of the recruitment of ubiquitin-binding effector p62/Sqstm1 is also controversial. One study showed that p62 plays a role in IFN-γ-mediated T. gondii clearance (74). On the other hand, another study demonstrated that p62 was not important in parasite clearance but was involved in presenting vacuolar antigens to CD8 T cells (73). Autophagy is another process that can discriminate between host membranes and T. gondii PVM. Autophagy is a self-degradative process that, for example, regenerates energy during embryonic development and in response to nutrient stress (77). Autophagy is tightly controlled by autophagy-regulated (ATG) genes (77). ATG8 is a ubiquitin-like protein required for the formation of autophagosomal membrane in yeast (78). Mammalian Atg8 consists of the LC3 subfamily such as LC3A and LC3B in addition to LC3C in humans and the GABARAP subfamily such as Gabarap, Gabarapl1 and Gate-16/Gabarapl2 (79). LC3B is a homologue of yeast Atg8 in mammals and accumulates on autophagosomes to remove intracellular pathogens from cells. Eventually, LC3-coated autophagosomes fuse with lysosomes (80). The autophagic process against pathogens is called xenophagy (81). LC3 also accumulates on the T. gondii PVM when cells are activated via CD40. CD40 stimulation might induce the activation of phosphoinositide-3-class 3 (PIK3C3), Rab7 and vacuolar ATPase to fuse PVM with late endosomes or lysosomes (82). However, LC3 recruitment to the T. gondii PV in response to IFN-γ treatment is controversial (34, 66, 83, 84) and it might be possible that autophagy is not functionally involved in anti-parasite immune responses mediated by IFN-γ. In autophagy, Atg12 and Atg5 form a complex that induces the conjugation of phosphatidylethanolamine (PE) on Atg8 (85). Cells lacking Atg5, an essential autophagy-related molecule, showed a defect in IFN-γ-mediated PV disruption, which is critical to prevent T. gondii replication (83). Because T. gondii PV or degraded parasites were not enveloped by double membranes, a hallmark of autophagy, the role of Atg5 in the IFN-γ-mediated anti-T. gondii response is independent of autophagy (86). Atg family members that belong to the Atg12 conjugation system, such as Atg3, Atg7 and Atg16L1, also participate in IFN-γ-mediated anti-T. gondii responses, but other Atg proteins that regulate the pathway containing ULK1, PI3K and Atg9 do not. Therefore, IFN-γ-mediated anti-T. gondii responses can be regulated by these Atg proteins in an autophagy-independent manner (72, 87, 88). Recently, we reported that a GABARAP subfamily member in the Atg8 family critically regulated the uniform cytosolic localization of GBPs, facilitating the efficient clearance of T. gondii. GBPs are localized at cytoplasmic vesicular-like structures and are equally distributed in IFN-γ-stimulated cells (68). Among GABARAP subfamily members, Gate-16 is the most important for GBP distribution, and its expression in LysM+ myeloid cells, mainly macrophages, neutrophils and monocytes, is essential for the survival of mice during the acute phase of T. gondii infection (34). Thus, the distribution of GBPs in the cytosol triggers the disruption of the PVM and is tightly regulated by autophagy proteins in an autophagy-independent fashion (Fig. 2). Conclusion Analysis of innate and adaptive immune responses to T. gondii has been extensively performed in mice and has elucidated various fundamental processes that have contributed to conceptual advances in immunology. Recent progress on cell-autonomous host defense has suggested there are still unidentified biological processes in anti-T. gondii immunity. Cell-autonomous immunity mediated by IFN-inducible GTPases such as GBPs and IRGs is important for anti-T. gondii responses as well as anti-bacterial immunity, where bacteria-containing vacuoles are disrupted by GBPs and IRGs in a similar fashion to T. gondii PVs (84, 89–91). This suggests a universal role for IFN-inducible GTPases in cell-autonomous immunity against vacuole-forming pathogens. In addition, the analysis of anti-T. gondii has revealed novel aspects of ILCs. Moreover, T. gondii secretes various virulence factors that suppress host immune responses (92, 93). The analysis of host factors targeted by virulence factors may reveal an unexpected immunological function of these factors or links between immunology and other fundamental biological fields. Thus, T. gondii will be a useful tool for immunological studies in the future. Funding Our work was supported by the Research Program on Emerging and Re-emerging Infectious Diseases (17fk0108120h0001) and the Japanese Initiative for Progress of Research on Infectious Diseases for Global Epidemics (17fm0208018h0001) from the Agency for Medical Research and Development (AMED), a Grant-in-Aid for Scientific Research on Innovative Areas (17K15677) from the Ministry of Education, Culture, Sports, Science and Technology, a Cooperative Research Grant of the Institute for Enzyme Research, Joint Usage/Research Center, Tokushima University, the Takeda Science Foundation, the Ohyama Health Foundation, the Heiwa Nakajima Foundation, the Cell Science Research Foundation, the Mochida Memorial Foundation on Medical and Pharmaceutical Research, the Senri Life Science Research Foundation and the Research Foundation for Microbial Diseases of Osaka University. Acknowledgement We thank M. Enomoto for secretarial and technical assistance. 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International ImmunologyOxford University Press

Published: Mar 1, 2018

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