Abstract Although Bach2 (broad complex-tramtrack-bric a brac and Cap’n’collar homology 2) plays an important role in regulating Th2 cell differentiation and type 2 immune responses, the underlying molecular mechanisms remain unclear. Our current studies demonstrate that Bach2 associates with Batf (basic leucine zipper transcription factor ATF-like) family transcription factors and binds to the regulatory regions of the Th2 cytokine gene loci. The Bach2–Batf complex antagonizes the recruitment of the interferon regulatory factor 4 (Irf4)-containing Batf complex to activator protein 1 (AP-1) motifs in the Th2 cytokine gene locus and suppresses Th2 cytokine production and/or Th2 cell differentiation. The deletion of Batf ameliorated the spontaneous development of type 2 airway inflammation that is found in mice with Bach2 deficiency specifically in T cells. Interestingly, Bach2 regulates Batf and Batf3 expression via two distinct pathways. First, the Bach2–Batf complex directly binds to the Batf and Batf3 gene loci and reduces transcription by interfering with the Batf–Irf4 complex. Second, Bach2 suppresses interleukin 4 (IL-4)-induced augmentation of Batf and Batf3 expression through the regulation of IL-4 production. These findings suggest that IL-4 and Batf family transcription factors form a positive feedback amplification loop to induce Th2 cell differentiation and that Bach2–Batf interactions block the formation of this amplification loop. Furthermore, we found that reductions in Bach2 confer an innate immunological function on CD4 T cells to induce antigen-independent cytokine production. Some Bach2-deficient lung CD4 T cells showed characteristic features similar to pathogenic Th2 cells, including IL-33 receptor expression and IL-33-dependent Th2 cytokine production. These results suggest a critical role for Bach2 in regulating Th2 cell differentiation and the subsequent onset of chronic type 2 inflammation. AP-1, Batf, IL-33, Il1rl1, Th2 Introduction Several functionally distinct CD4 T-cell subsets have been reported, including Th1, Th2, Th17, follicular helper T (Tfh) and inducible regulatory T (iTreg) cells (1–8). Among these populations, Th2 cells play a crucial role in regulating type 2 immune responses and the pathogenesis of type 2 inflammation. Therefore, elucidating the molecular mechanisms by which naive CD4 T cells differentiate into Th2 cells is important for understanding the onset of type 2 chronic airway inflammation. Gata3, a master regulator of Th2 cell differentiation, is induced through the activation of the interleukin4 (IL-4)/Stat6-dependent signaling pathway in peripheral CD4 T cells and binds to several regulatory regions in the Th2 cytokine gene locus, inducing chromatin remodeling (9, 10). The murine Th2 cytokine genes encoding IL-4, IL-5 and IL-13 are located within a 140-kb region on chromosome 11 flanking the Rad50 genes (10). Several regulatory regions of the Th2 cytokine gene locus have been reported (10). The locus control region (LCR) for the Th2 cytokine gene locus has been mapped to a region of ~25 kb within the 3′ intronic regions of the Rad50 genes (11). The intron 2 region of the Il4 gene [DNase I hypersensitive site 2 (HS2), Il4 intronic enhancer (Il4 IE)], a Gata3-binding site, is crucial for the production of IL-4 by Th2 cells (12), and the deletion of the Il4 IE site results in a reduction in IL-4 production, but not that of IL-5 or IL-13, in Th2 cells. The conserved Gata3 response element (CGRE) upstream of the Il13 gene locus is important for controlling widespread chromatin modifications of the Il13 and Il4 gene loci (13) and the deletion of the CGRE site resulted in the reduced generation of IL-13-producing Th2 cells (12). Bach [broad complex-tramtrack-bric a brac (BTB) and cap’n’collar (CNC) homology] proteins are transcriptional repressors of the bZIP (basic leucine zipper) transcription factor family (14–16). It is well established that Bach transcription factors form heterodimers with sMaf [small Maf (musculoaponeurotic fibrosarcoma oncogene homolog)] bZip transcription factors such as MafF, MafG and MafK (16, 17). Complexes of sMaf and Bach proteins recognize the consensus DNA sequences for nuclear factor, erythroid 2 (NF-E2), NF-E2-related factor (Nrf) and activator protein 1 (AP-1) families (18). Bach2 is highly expressed in B cells and T cells, whereas Bach1 expression is predominant in monocytes, macrophages, neutrophils and dendritic cells (17). Bach2 plays a critical role in somatic hypermutation and class-switch recombination (19–21) and regulates the formation of IgG1+ memory B cells (22). Recently, Itoh-Nakadai et al. reported that Bach2 promotes B-cell development via the repression of the myeloid program (23, 24). Bach2 also contributes to T-cell-mediated immune responses and participates in Treg-mediated immune homeostasis, and Bach2-null animals suffer from lethal lung and small intestinal inflammation (25, 26). Bach2 is required for suppressing the expression of genes related to effector memory T cells in naive CD4 T cells (27). Bach2 deficiency in CD4 T cells reduces the number of naive CD4 T cells and increases the number of Th2-type effector memory T cells. In addition, Bach2 plays an important role in the formation of memory CD8 T cells (28). We previously demonstrated that Bach2-deficient CD4 T cells that are activated in vitro preferentially differentiate into Th2 cells with a senescence-associated secretory phenotype (SASP) (29). Furthermore, polymorphisms of the human BACH2 gene are associated with multiple inflammatory diseases including asthma (30, 31). These findings establish Bach2 as a key regulator of adaptive immune responses. However, the molecular mechanisms by which Bach2 controls Th2 cell function and differentiation have yet to be fully elucidated. Basic leucine zipper transcription factor ATF-like (Batf) family transcription factors belong to the AP-1 family of transcription factors (32). The Batf family comprises three transcription factors—Batf, Batf2 and Batf3—which are composed of only a DNA-binding domain and a leucine zipper motif. These factors were originally identified as inhibitors of AP-1-dependent transcriptional activation (33, 34). A recent study revealed that Batfs interact with interferon-regulatory factor (Irf) family proteins including Irf4 and activate Irf-mediated transcription (35, 36). Batf is required for the differentiation and functions of Th2, Th17 and Tfh cells, and Batf3 regulates Th2 cell function (32). In the present review, we discuss how Bach2 associates with Batf and regulates chronic type 2 inflammation following Th2 cell differentiation. Bach2 expression in T cells controls the severity of type 2 airway inflammation A recent meta-analysis of worldwide asthma genome-wide association studies revealed that a single-nucleotide polymorphism (SNP) of the BACH2 gene locus was closely associated with a risk of asthma (31). In addition, the existence of a syndrome of BACH-related immunodeficiency and autoimmunity that results from BACH2 haploinsufficiency was reported (37). We previously found that transgenic (TG) mice with Bach2 deficiency specific for T cells (Bach2flox/flox mice with CD4-Cre transgene) spontaneously developed type 2 airway inflammation (38). In that study, the increased infiltration of inflammatory cells, especially eosinophils and lymphocytes, was noted in the bronchoalveolar lavage (BAL) fluid of the T-cell-specific Bach2-deficient mice compared with control wild-type (WT) mice. The bronchioles of the Bach2-deficient mice showed mucus hyper-production, goblet cell metaplasia and pulmonary fibrosis were detected in the lungs of Bach2-deficient mice. Methacholine-induced airway hyper-responsiveness was also observed in Bach2-deficient mice. The numbers of IL-5-producing and IL-13-producing CD4 T cells were significantly increased in the lungs, but not in the spleen, of Bach2-deficient mice compared with the control WT mice. The spontaneous development of airway inflammation and the increased production of Th2 cytokines (IL-4, IL-5 and IL-13) in lung CD4 T cells of Bach2-deficient mice were ameliorated by the deletion of Stat6, supporting a role for this feature of type 2 airway inflammation. The inhibitory role of Bach2 in the type 2 immune response was demonstrated using T-cell-specific Bach2 TG (Rosa26-Stop cassetteflox/flox-Bach2 TG mice crossed with CD4-Cre TG) mice (in which T cells over-express Bach2). The differentiation of Th2 cells and Th2 cytokine production in vitro was significantly decreased in Bach2 TG naive CD4 T cells. Symptoms of ovalbumin (OVA)-induced type 2 airway inflammation including the infiltration of eosinophils into the BAL fluid, mucus hyper-production and goblet cell metaplasia were reduced in T-cell-specific Bach2 TG mice. The dysregulated development of Foxp3+ CD4 T cells in Bach2-null mice was previously reported (26, 39). Furthermore, the numbers of FOXP3+ Treg cells in the colon of BACH2 haploinsufficiency patients were significantly reduced compared with those in healthy controls (37). The number of Foxp3+ CD4 T cells in the thymus of T-cell-specific Bach2-deficient mice was decreased to half, and the induction of Foxp3+ cells from Bach2-deficient naive CD4 T cells was severely decreased in vitro. However, T-cell-specific Bach2-deficient mice had similar numbers of Foxp3+ CD4 T cells in the lungs as control WT mice did. Furthermore, the generation of Foxp3+ cells in Bach2 TG naive CD4 T cells in vitro was comparable to that of WT naive CD4 T cells. However, the immune suppressive activity of Bach2-deficient Treg cells was not assessed and the molecular mechanism underlying the Bach2-mediated regulation of Foxp3 expression remains unclear. The inhibitory function of the Bach2–Batf complex in the type 2 immune response Bach2 interacts with Batf and inhibits AP-1-dependent gene activation We next examined how Bach2 controls Th2 cell differentiation and/or function in CD4 T cells. The CNC gene family consists of two transcriptional repressors (Bach1 and Bach2) and four activators (Nfe2, Nrf1, Nrf2 and Nrf3) (14, 15). Bach2 interacts with sMaf proteins and acts as a genetic inhibitor of the gene expression directed by the TPA response element (TRE), the Maf recognition element (MARE) and the antioxidant response element (ARE) (16, 40). Although Bach2 plays a crucial role in T-cell-mediated immune responses (25, 27, 29), the role of sMaf proteins in T-cell-mediated immune responses has not yet been established. To identify Bach2-binding sites in effector CD4 T cells, we performed chromatin immunoprecipitation (ChIP)-sequencing with an anti-Bach2 antibody and found that the binding of Bach2 is enriched predominantly in the motifs for AP-1, Nrf/Maf/MARE, Atf4 and Batf. The majority of enriched motifs contain the AP-1 consensus DNA sequence [TGA(G/C)TCA]. The binding of Bach2–Batf complexes was confirmed by an oligonucleotide pull-down analysis with an AP-1 consensus oligonucleotide. Furthermore, Bach2 repressed the PMA-induced AP-1 luciferase activity in 293 T cells. Similarly, an inhibitory effect of Bach2 on AP-1-dependent Il2 gene transcription in CD4 T cells was reported (41). Bach2 also regulates CD8 T-cell differentiation by controlling the accessibility of AP-1 factors to enhancers (18). Bach2 recruits AP-1-containing enhancers, subsequently limiting the expression of TCR-driven genes by restricting the accessibility of AP-1 sites. Thus, Bach2 binds to AP-1 motifs and inhibits AP-1-dependent gene activation. However, the molecular mechanism by which Bach2 binds to the AP-1 motif and suppresses AP-1 function remains to be elucidated. We screened Bach2 interaction transcriptional modulators using an amplified luminescent proximity homogenous assay (AlphaScreen) with cell-free technology for protein synthesis as previously described (42, 43) and Batf and Batf3 were identified as potential candidates for Bach2-interacting transcription factors. The association of Bach2 with Batf or Batf3 was confirmed by co-precipitation assay, and the leucine zipper of both proteins was found to be responsible for the interaction. The oligonucleotide precipitation assay with the AP-1 consensus motif demonstrated the binding of the Bach2–Batf complex to the AP-1 sequence. T-cell-specific deletion of Batf normalizes the augmented type 2 immune response in Bach2-deficient mice We next examined whether or not Bach2–Batf interactions control Th2 cell differentiation and/or Th2 cytokine production. A series of ChIP analyses revealed that Bach2 binds to the Il4 IE, the RHS6 (Rad50 hypersensitive site 6) located within the Th2 LCR and the 3′ downstream region of the Il5 gene. A significant reduction in the Bach2 binding to these regions was noted in Batf-deficient activated CD4 T cells indicating the Batf-dependent binding of Bach2. The Batf–Jun complex is reportedly associated with Irf4 and positively regulates transcription (35). In addition, the binding of the Batf–Irf4 complex to enhancers in Th2 cells is determined by the quality of TCR signaling (44). The binding of Batf, JunD and Irf4 to the RHS6 and Il4 IE regions was significantly increased in Bach2-deficient activated CD4 T cells. These results imply that Bach2–Batf complexes bind to the AP-1 motif-containing regulatory regions of the Th2 cytokine gene locus and antagonize the recruitment of Batf–Irf4 active complexes. A ChIP-sequencing also revealed that Bach2 binds to the Nrf2 sites of the Th2 cytokine gene locus (38), and Th2 skewing by activation of Nrf2 has been reported (45). Therefore, it is possible that Bach2–Batf complexes also bind to the Nrf2 sites and antagonize the recruitment of Nrf2 complexes. The increased infiltration of mononuclear cells into the peribronchiolar regions of the lungs, and mucus hyper-production and goblet cell metaplasia observed in Bach2-deficient mice were ameliorated by Batf deletion. The increased infiltration of eosinophils, neutrophils and lymphocytes in the BAL fluid of Bach2-deficient mice was also significantly reduced in Bach2/Batf double-deficient mice. Furthermore, an increased production of Th2 cytokines (IL-4, IL-5 and IL-13) in lung CD4 T cells of Bach2-deficient mice was reduced by Batf deletion. The increased generation of IL-4-producing Th2 cells in Bach2-deficient mice was also significantly reduced by Batf deficiency in vitro. Given these findings, we conclude that Bach2–Batf complexes suppress Th2 cell differentiation and subsequent type 2 inflammation (Fig. 1). Fig. 1. View largeDownload slide The Bach2–Batf complex interferes with the recruitment of active AP-1 complexes to the AP-1 motifs at the Th2 cytokine gene locus. Decreased Bach2 levels enhance the AP-1-dependent activation of the Th2 cytokine gene locus and augment Th2 cell differentiation and/or Th2 cytokine production. Fig. 1. View largeDownload slide The Bach2–Batf complex interferes with the recruitment of active AP-1 complexes to the AP-1 motifs at the Th2 cytokine gene locus. Decreased Bach2 levels enhance the AP-1-dependent activation of the Th2 cytokine gene locus and augment Th2 cell differentiation and/or Th2 cytokine production. IL-4 and Batf–Irf4 form a positive feedback loop to induce Th2 cell differentiation, and Bach2–Batf interactions interfere with this amplification loop The IL-4/Stat6-dependent maintenance of Batf, Batf3 and Irf4 expression was reported previously (46). However, the sustained mRNA expression of Batf and Batf3 in TCR-stimulated Bach2-deficient naive CD4 T cells showed only a partial reduction after Stat6 deletion. A decreased expression of Batf and Batf3 mRNA was observed in Bach2 TG CD4 T cells even in the presence of IL-4. Bach2 binding to the Batf and Batf3 gene loci was detected, and the binding of Batf and Irf4 to the Bach2-binding sites within the Batf and Batf3 gene loci was significantly increased in Bach2-deficient CD4 T cells. Furthermore, the tri-methylation levels of histone H3K4, an active gene marker, at the transcription starting sites of Batf and Batf3 were elevated in the Bach2-deficient effector CD4 T cells. IL-4/Stat6 signaling also inhibited Bach2 expression, indicating that the activation of the IL-4/Stat6 signaling pathway induces the sustained formation of the Batf–Irf4 complex (and Batf3–Irf4). Given these findings, we conclude that IL-4 and Batf–Irf4 form a positive feedback loop to induce Th2 cell differentiation, and Bach2–Batf interactions interfere with this amplification loop (Fig. 2). Fig. 2. View largeDownload slide Bach2–Batf interactions inhibit the formation of the IL-4 amplification loop to induce Th2 cell differentiation and the subsequent onset of Th2-type chronic inflammation. Fig. 2. View largeDownload slide Bach2–Batf interactions inhibit the formation of the IL-4 amplification loop to induce Th2 cell differentiation and the subsequent onset of Th2-type chronic inflammation. The increased expression of IL-33 receptor in lung CD4 T cells may be involved in the spontaneous development of airway inflammation in T-cell-specific Bach2-deficient mice The cross-talk between epithelial cells, dendritic cells, innate lymphoid cells (ILCs) and CD4 T cells plays an important role in the pathogenesis of asthma (47, 48). Three epithelium-derived cytokines, namely IL-25, IL-33 and thymic stromal lymphopoietin (TSLP), contribute to the cross-talk. These cytokines influence allergic mechanisms that include activating type 2 ILCs, Th2 cell development and eosinophils (47, 49, 50). Among epithelium-derived cytokines, IL-33 is particularly interesting because of the reported associations between asthma and both IL-33 and its receptor (51, 52). We found that IL-33 receptor α (IL-33Rα)+ lung CD4 T-cell numbers were increased in Bach2-deficient mice (38). The increased cell surface expression of IL-33Rα was marginal on CD4 T cells in other organs. Both WT and Bach2-deficient IL-33Rα+ lung CD4 T cells express high-level Th2 cytokine mRNA in response to TCR stimulation indicating that IL-33Rα+ lung CD4 T cells have characteristic features similar to those of pathogenic Th2 cells (48, 53). The expression of Bach2 mRNA in IL-33Rα+ lung CD4 T cells was significantly lower than in IL-33Rα– cells. Gata3 reportedly plays a critical role in the induction of Il1rl1 (IL-1 receptor-like 1; this encodes IL-33Rα) expression in Th2 cells (54). IL-33R-expressing Th2 cells have an innate immunological function to produce IL-5 and IL-13 but not IL-4 in response to IL-33 plus Stat5 activators, such as IL-2 and IL-7 in vitro and in vivo (54, 55). We found that Bach2-deficient lung CD4 T cells produced IL-5 and IL-13 in response to IL-33 plus IL-7 (M.Y., unpublished data). Furthermore, ChIP-sequencing revealed that Bach2 binds to the Il1rl1 gene locus and inhibits Il1rl1 mRNA expression. Thus, the reduction of Bach2 confers an innate immunological function on Th2 cells via the epigenetic regulation of the Il1rl1 and Th2 cytokine gene loci. Conclusion Recent reports on Bach2 have clearly shown the critical role of Bach2 in Th2 cell-mediated immune responses. Bach2 inhibits type 2 immune responses via multiple pathways (Fig. 3). First, Bach2 associates with Batf and binds to the LCR of the Th2 cytokine gene locus, thereby inhibiting Th2 cytokine production and/or Th2 cell differentiation. Second, Bach2 is required for the development of Foxp3+ Treg cells, although the molecular mechanism underlying the Bach2-mediated regulation of Treg cells remains to be elucidated. Third, Bach2 suppresses Il1rl1 transcription and inhibits the generation of IL-33Rα+ CD4 T cells that produce IL-5 and IL-13 in response to IL-33 and IL-7 in an antigen-independent manner. Thus, T-cell-specific Bach2 deficiency results in the spontaneous development of type 2 lung inflammation. Fig. 3. View largeDownload slide Bach2 inhibits the Th2-dependent immune response via multiple pathways. Fig. 3. View largeDownload slide Bach2 inhibits the Th2-dependent immune response via multiple pathways. It was recently reported that the PI3K–Akt–mTOR (phosphoinositide 3-kinase–Ak-strain thymoma oncogene–mechanistic target of rapamycin) pathway inhibits Bach2 by repressing both its expression and its nuclear translocation in B cells (56). The expression and cellular localization of Bach2 in T cells is also likely regulated by TCR-dependent or cytokine-dependent activation of this pathway. Indeed, the level of Bach2 is lower in CD44high lung CD4 T cells than in CD44low cells. 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International Immunology – Oxford University Press
Published: Feb 24, 2018
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