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Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria–specific CD4+ T cells

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Science  29 May 2015:
Vol. 348, Issue 6238, pp. 1031-1035
DOI: 10.1126/science.aaa4812

Innate lymphoid cells keep gut T cells in check

Trillions of bacteria inhabit our guts. So do many types of immune cells, including T cells, which might be expected to attack these bacteria. How, then, do our bodies manage to keep the peace? Working in mice, Hepworth et al. report one such mechanism. A population of immune cells, called innate lymphoid cells, directly killed CD4+ T cells that react to commensal gut microbes. Some of the specifics of this process parallel how the immune system keeps developing self-reactive T cells in check in the thymus. Furthermore, this peacekeeping process may be disrupted in children with inflammatory bowel disease.

Science, this issue p. 1031

Abstract

Inflammatory CD4+ T cell responses to self or commensal bacteria underlie the pathogenesis of autoimmunity and inflammatory bowel disease (IBD), respectively. Although selection of self-specific T cells in the thymus limits responses to mammalian tissue antigens, the mechanisms that control selection of commensal bacteria–specific T cells remain poorly understood. Here, we demonstrate that group 3 innate lymphoid cell (ILC3)–intrinsic expression of major histocompatibility complex class II (MHCII) is regulated similarly to thymic epithelial cells and that MHCII+ ILC3s directly induce cell death of activated commensal bacteria–specific T cells. Further, MHCII on colonic ILC3s was reduced in pediatric IBD patients. Collectively, these results define a selection pathway for commensal bacteria–specific CD4+ T cells in the intestine and suggest that this process is dysregulated in human IBD.

Pathologic CD4+ T cell responses to self are limited by presentation of self-antigens in the thymus on major histocompatibility complex class II–positive (MHCII+) thymic epithelial cells (TECs) and dendritic cells (DCs), resulting in clonal deletion (16). In contrast, commensal bacteria–specific CD4+ T cells, which have been implicated in the pathogenesis of inflammatory bowel disease (IBD) (711), do not encounter cognate antigen in the thymus and therefore are not subject to negative selection before entering the periphery (12, 13). Although physical and biochemical barriers separate the immune system from intestinal commensal bacteria (7, 1317), antigens derived from commensal bacteria are continuously sampled from the intestinal lumen and presented by DCs in the draining lymph nodes (7, 10, 15, 18, 19). Regulatory T cells (Treg) can in part limit dysregulated CD4+ T cell responses to commensal bacteria (20, 21). However, whether other mechanisms control commensal bacteria–specific CD4+ T cells in lieu of thymic negative selection is poorly defined. In recent studies, group 3 innate lymphoid cells (ILC3s) were found to express MHCII, and genetic deletion of ILC3-intrinsic MHCII resulted in spontaneous CD4+ T cell–dependent intestinal inflammation (22), suggesting that additional antigen-presentation pathways control commensal bacteria–specific CD4+ T cell populations.

CCR6-expressing lymphoid tissue inducer (LTi)–like ILC3s (CCR6+ ILC3s) are a major ILC subset present in the mesenteric lymph node (mLN) (Fig. 1A) and colon lamina propria (cLPL) (fig. S1A) of healthy mice and constitutively express retinoic acid–related orphan receptor gamma t (RORγt) and MHCII, relative to ST2+ group 2 ILCs (ILC2) (fig. S1, B and C). ILC3s are regulated by various cytokine, environmental, and microbial factors (23, 24). However, interleukin (IL)–23p19, the aryl hydrocarbon receptor (Ahr), or the intestinal microbiota were not required for CCR6+ ILC3 expression of MHCII (fig. S1, D to F), although ILC3 frequencies were reduced in the intestine of Ahr−/− mice, as previously described (fig. S1E) (25). Further, in contrast to a recent report (26), expression of MHCII, CD80, and CD86 on CCR6+ ILC3s was unaffected by ex vivo stimulation with microbial or inflammatory stimuli or by the absence of MyD88 or Caspase 1/11 in vivo (fig. S2).

Fig. 1 ILC3 expression of MHCII is controlled by a transcriptional pathway previously associated with thymic epithelial cells.

(A) mLN cells from naïve mice were gated as CD45+ lineage (x axis: CD3, CD5, CD8, and NK1.1; y-axis: B220, CD11c, and CD11b) negative, CD25+, and CD127+ and further divided by expression of ST2 (ILC2, red) or CCR6 (ILC3, blue). MHCII expression was determined on ILC3s in mice deficient in (B) CIITA, (C) CIITA promoter regions (pIII/pIV and pIV) or (D) IFN-γ and IFN-γR1. All data are representative of at least three independent experiments with n = 2 to 3 mice per group.

Next, we examined whether expression of ILC3-intrinsic MHCII was dependent on the class II transactivator (CIITA), a master transcriptional regulator of MHCII expression (27). MHCII expression was absent on both CCR6+ ILC3s and canonical antigen-presenting cells from Ciita−/− mice, relative to Ciita+/+ control mice (Fig. 1B and fig. S3A). Transcription of CIITA in mice is driven via distinct promoter elements—termed pI, pIII, and pIV—that are indicative of the upstream signaling events that induce MHCII expression (27). In contrast to B cells and DCs, CCR6+ ILC3-intrinsic MHCII expression was absent in the mLN of both pIII/pIV−/− and pIV−/− mice (Fig. 1C and fig. S3, B and C), indicating that the pIV promoter of Ciita is required for MHCII expression on CCR6+ ILC3s. The pIV promoter of Ciita is used by multiple cell types, such as epithelial cells, in response to interferon (IFN)–γ signaling (27). However, expression of MHCII on CCR6+ ILC3s was not impaired in the absence of IFN-γ, IFN-γR1, or STAT-1 (Fig. 1D and fig. S3, D and E). MHCII expression in TECs was also dependent on the pIV promoter of Ciita (fig. S3, A and B), and pIV-dependent, IFN-γ–independent CIITA expression has previously only been described in TECs (2729), suggesting a previously unappreciated link between ILC3s and TECs.

These data provoked the hypothesis that TECs and MHCII+ ILC3s may share similar functional roles in the selection of CD4+ T cells. To test this, we examined CD4+ T cells in the intestines of mice with an ILC3-intrinsic deletion in MHCII (MHCIIΔILC3 mice). As we previously reported (22), frequencies and cell numbers of CD44hi CD4+ T cells (Teff) in the cLPL of MHCII∆ILC3 mice were increased relative to H2-Ab1fl/fl controls (fig. S4, A and B). In contrast, the total numbers of CD44lo naïve T cells and FoxP3+ Treg were unchanged (fig. S4B). Teff cell populations used a broad range of T cell receptor (TCR) Vβ chains, and Teff expansion was detected in the cLPL but not in the thymus (fig. S4C). Further, sort-purified CD4+ T cells from MHCII∆ILC3 mice responded to fecal-derived antigen but not mammalian tissue-derived antigens (fig. S4D).

These data, along with previous studies (20, 30, 31), suggest that the majority of CD4+ T cells in the steady-state intestine are specific for commensal bacteria and that ILC3-intrinsic MHCII controls commensal bacteria–specific CD4+ T cell responses through direct presentation of microbiota-derived antigens. To test this, we crossed MHCII∆ILC3 mice with either TCR transgenic mice specific for CBir1, an antigen expressed by Clostridia species constitutively present in the murine and human microbiota (13, 32), or TCR transgenic mice specific for ovalbumin (OT-II). Loss of ILC3-intrinsic MHCII had no effect on the frequencies or cell numbers of OT-II or CBir1 T cells in the thymus (Fig. 2A). In contrast, numbers of CBir1, but not OT-II, T cells were increased in the cLPL and mLN (Fig. 2B and fig. S5A), and CBir1MHCII∆ILC3 mice exhibited increased frequencies of antigen-specific IFN-γ+ and tumor necrosis factor (TNF)–α+ colonic CD4+ T cells, colonic inflammation, and neutrophil infiltration, which could be prevented by administration of antibiotics (ABX) and was not observed in Rag1−/− MHCII∆ILC3 mice (Fig. 2B-D and fig. S5A-D). Finally, similar to polyclonal MHCII∆ILC3 mice, the population expansion and increased cytokine production of CBir1 CD4+ T cells were associated with a selective increase in CD44hiCD62Llo Teff, whereas numbers of FoxP3+ Treg remained unchanged (fig. S5E). These data suggest that CCR6+ ILC3s selectively limit the expansion of commensal bacteria–specific CD4+ effector T cells through presentation of antigen derived from the endogenous microbiota. In support of this hypothesis and consistent with recent findings (33), MHCII+ ILC3s localized in distinct clusters in the mLN at the interface between the B and T cell zones in the marginal and subcapsular sinus (Fig. 2E), a site through which antigen-experienced T cells traffic.

Fig. 2 MHCII+ ILC3s induce deletion of commensal bacteria–specific CD4+ T effector cells in the intestine and associated lymph nodes.

Total Vβ5+ (OT-II) or Vβ8.3+ (CBir1) CD4+ T cell numbers determined in (A) the thymus and (B) cLPL of control (H20) or antibiotic (ABX)–treated OT-II and CBir1 transgenic mice crossed with MHCII∆ILC3 mice or H2-Ab1fl/fl littermate controls. (C) Colon histology (scale bar, 200 μm) and (D) frequencies of (CD45+ B220 CD3) Ly6C+ Ly6G+ neutrophils in the cLPL of CBir1MHCII∆ILC3 and CBir1H2-Ab1fl/fl mice. (E) Immunofluorescence imaging of mLN sections stained for CD3 (blue), RORγt (green), MHCII (red), or 4′,6-diamidino-2-phenylindole (DAPI) (gray). White arrows indicate RORγt+ cell clusters. Scale bar, 200 μm. (Inset) Colocalization of RORγt+ MHCII+ ILCs and CD3+ T cells. Scale bar, 10 μm. (F) MHCII expression was restricted to RORγt+ ILC3s (MHCIIILC3+ mice) by crossing RorcCre mice with IAβbSTOPfl/fl (MHCIIneg) mice, and (G) MHCII levels were determined on B220+ B cells, CD11b+ CD11chi DCs, CD11b+ F4/80+ macrophages (Macs), or Linneg CD25+ CD127+ CCR6+ ILC3s in the mLN of heterozygote littermates (IAβbSTOP+/fl and MHCIIpos), MHCIIneg, or MHCIIILC3+ mice. (H to K) MHCIIneg and MHCIIILC3+ received preactivated CD45.1+ CBir1 transgenic CD4+ T cells and were injected with CBir1 peptide intraperitoneally every 2 days. Frequencies and numbers of transferred T cells were analyzed in the mLN [(H) and (I)], siLPL and cLPL 9 days after transfer [(J) and (K)]. All data are representative of at least four independent experiments with n = 2 to 3 mice per group. Results are shown as the mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 (two-tailed Student’s t test).

To investigate the in vivo mechanisms through which MHCII+ ILC3s control commensal bacteria–specific CD4+ T cells, mice were generated in which MHCII expression was restricted to only ILC3s (Fig. 2F). This was accomplished by using mice with a floxed-STOP sequence cassette inserted between the first and second IAβb exons (IAβbSTOPfl/fl mice) (34). IAβbSTOPfl/fl mice lack MHCII on antigen-presenting cells in the absence of Cre recombinase (MHCIIneg) (Fig. 2G). In contrast, IAβbSTOPfl/fl mice crossed with RorcCre mice demonstrated a partial restoration of MHCII on CCR6+ ILC3s (MHCIIILC3+ mice) but not B cells, DCs, or macrophages (Fig. 2G). As MHCIIneg and MHCIIILC3+ mice lack MHCII on TECs and have disrupted endogenous T cell selection (34), we first employed an adoptive transfer approach with naïve carboxyfluorescein diacetate succinimidyl ester (CFSE)–labeled CD45.1+ CBir1 T cells. In mice with normal MHCII expression (MHCIIpos), administration of CBir1 peptide resulted in dilution of CFSE in transferred CBir1 T cells, expansion of CD44hiCD62Llo CBir1 Teff cells, and an increase in FoxP3+ Treg in the mLN (fig. S6A). In contrast, naïve CBir1 CD4+ T cells transferred into control MHCIIneg and MHCIIILC3+ mice failed to proliferate or differentiate into Teff or Treg after peptide administration (fig. S6A), suggesting that ILC3-intrinsic MHCII does not influence naïve CD4+ T cells. As MHCII+ ILC3s localize at lymphoid sites through which antigen-experienced CD4+ T cells traffic (Fig. 2E) (33), CBir1 CD4+ T cells were preactivated overnight before transfer into MHCIIneg or MHCIIILC3+ mice. After CBir1 peptide administration, MHCIIILC3+ mice exhibited reduced frequencies and numbers of preactivated CBir1 CD4+ T cells in the mLN (Fig. 2, H and I), which was due to a selective decrease in effector, but not regulatory CBir1 T cells (Fig. 2I). MHCII+ ILC3-mediated effects were antigen-specific, could be driven by endogenous microbiota-derived antigen alone, and were specific to ILC3s (fig. S6, B to D, and fig. S7). Further, in complementary loss-of-function studies, adoptively transferred CBir1 CD4+ Teff expanded at higher frequencies and numbers in the mLN and cLPL of mice lacking ILC3-intrinsic MHCII (MHCII∆ILC3 mice), despite exhibiting comparable proliferation (fig. S8). Finally, in line with ILC3-mediated control of antigen-experienced T cells, the frequency and number of activated CBir1 CD4+ T cells reaching the small intestine lamina propria (siLPL) and cLPL of MHCIIILC3+ mice were significantly decreased relative to MHCIIneg controls (Fig. 2, J to K).

We hypothesized that the loss of CBir1 CD4+ T cells from the mLN and intestine of MHCIIILC3+ mice could be the result of altered migration, proliferation, or induction of cell death. However, preactivated CBir1 T cells did not accumulate in peripheral organs, such as the spleen (fig. S9A), and CBir1 T cells recovered from MHCIIILC3+ mice exhibited comparable proliferation relative to MHCIIneg mice (fig. S9B). To further investigate this question, we developed an in vitro ILC3-CD4+ T cell coculture system. Consistent with our in vivo findings, coculture of activated CBir1 T cells and sort-purified MHCII+ CCR6+ ILC3s resulted in a significant reduction in T cell numbers after culture in the presence of cognate antigen, which could be reversed by administration of an MHCII-blocking antibody (Fig. 3A). Reduced cell recovery was associated with an antigen and MHCII-dependent increase in Caspase-3 activation (Fig. 3B) and increased Annexin V staining (Fig. 3C), indicative of programmed cell death. Despite selectively regulating commensal bacteria–specific CD4+ T cells in the steady state, MHCII+ ILC3s were also sufficient to influence T cells with other antigen specificities only if antigen was exogenously provided (fig. S10).

Fig. 3 MHCII+ ILC3s directly induce cell death of commensal bacteria–specific CD4+ T cells.

(A to D) Activated CBir1 CD4+ T cells were cocultured with sort-purified CCR6+ ILC3s in the presence or absence of CBir1 antigen or a neutralizing antibody to MHCII, and (A) T cell recovery (%) was quantified relative to T cells cultured alone, (B) frequency of active Caspase-3–expressing T cells was assessed, and (C) frequencies of Annexin V+ dead-cell exclusion dye-negative (preapoptotic) T cells were quantified. (D) Expression of Nur77 by CBir1 CD4+ T cells and (E) expression of Bim by preactivated CBir1 CD4+ T cells after 24 hours (D) or 48 hours (E) coculture with antigen-pulsed MHCII+ ILC3s in the presence or absence of a neutralizing antibody to MHCII. Mean fluorescent intensity (MFI) values are shown in italics. (F and G) Bim+/+ or Bim−/− CBir1 T cells were cocultured with ILC3s in the presence or absence of CBir1 antigen for 48 hours, and (F) relative T cell recovery (%) and (G) frequencies of Annexin V+ preapoptotic cells were quantified. (H) Heat map of selected candidate genes from mLN-derived CCR6+ ILC3s. (I) Relative T cell recovery (%) of wild-type (WT) CBir1 CD4+ T cells cocultured with antigen-pulsed ILC3s in the presence or absence of exogenous rIL-2 or rIL-7. (J and K) Activated CBir1 CD4+ T cells with WT or constitutively active (CA) STAT-5 signaling were cocultured with ILC3s in the presence or absence of CBir1 antigen for 48 hours, and (J) relative T cell recovery (%) and (K) frequencies of Annexin V+ preapoptotic T cells were quantified. (L) WT CBir1 CD4+ T cells or CBir1 STAT5-CA CD4+ T cells were adoptively transferred into MHCIIneg or MHCIIILC3+ mice. Mice were administered CBir1 antigen, and numbers of FoxP3 CD45.1+ CBir1 T cells in the cLPL were quantified 9 days after transfer. In vitro assay data are representative of at least two to three independent experiments, with two to three biological replicates per experiment. Array data are representative of a single experiment with four biological replicates. All in vivo data are representative of at least two independent experiments with at least n = 3 mice per group. Results are shown as the mean ± SEM. *P < 0.05; **P < 0.01; ***P < 0.001 (two-tailed students t test).

Negative selection in the thymus has been shown to be associated with induction of Nur77 and up-regulation of the proapoptotic molecule Bim (35), which together mediate clonal deletion. Presentation of antigen by MHCII+ ILC3s also resulted in the up-regulation of Nur77 and Bim by CBir1 CD4+ T cells, the latter of which was required for ILC3-mediated induction of T cell death (Fig. 3D-G). Antigen presentation by ILC3s in vitro selectively led to Teff death but did not affect Treg numbers (fig. S11A). We next analyzed mLN-derived CCR6+ ILC3 for expression of surface molecules that directly influence antigen-specific CD4+ T cell responses (Fig. 3H). ILC3s demonstrated high levels of MHCII-associated transcripts but had negligible expression of transcripts for canonical costimulatory molecules and inhibitory or death receptors (Fig. 3H). Indeed, CCR6+ ILC3s lacked expression of FasL by flow cytometry, and antibody-mediated neutralization of FasL did not influence ILC3-induced CBir1 T cell death (fig. S11, B to D). Moreover, in contrast to Bim−/− mice, faslgld/gld mice did not exhibit increased frequencies of endogenous commensal bacteria–specific CD4+ T cells in gut-associated lymphoid tissues (fig. S11E).

Bim-dependent apoptotic cell death may also be induced via cytokine or growth factor starvation (36, 37). Because CCR6+ ILC3s constitutively express high levels of the common gamma chain cytokine receptors CD25 (IL-2R) and CD127 (IL-7Rα) (Fig. 1, fig. S1 and Fig. 3H), we hypothesized that MHCII+ ILC3s may induce cell death of commensal bacteria–specific CD4+ T cells synergistically through TCR induction of an apoptotic program in concert with cytokine withdrawal. Consistent with this, cell death could be reduced upon addition of exogenous recombinant (r)IL-2, but not rIL-7, to in vitro cocultures (Fig. 3I). MHCII+ ILC3s exhibited more than twofold higher capacity to bind IL-2 as compared with activated CBir1 CD4+ T cells (fig. S11, F and G), suggesting that MHCII+ ILC3s outcompete activated T cells for prosurvival cytokines. The requirement for IL-2 was T cell–intrinsic as activated CBir1 CD4+ T cells expressing a constitutively active STAT-5 molecule (S5CA) were resistant to Bim up-regulation and ILC3-induced cell death in vitro and in vivo (Fig. 3, J to L, and fig. S11, H and I). Taken together, these data indicate that MHCII+ ILC3s mediate a negative selection process through antigen presentation and withdrawal of IL-2 from the local milieu, resulting in deletion of activated commensal bacteria–specific T cells.

Inflammatory CD4+ T cell responses against commensal bacteria are causally associated with the pathogenesis of IBD (711). Furthermore, inflammatory T cells derived from Crohn’s disease patients also exhibit reduced Bim-mediated cell death and cytokine-withdrawal–mediated apoptosis (38, 39). Therefore, we next examined whether ILC3-intrinsic MHCII may be dysregulated in the context of human IBD. Using a previously defined gating strategy (40), all ILC subsets could be identified in intestinal biopsies of pediatric Crohn’s disease patients (Fig. 4A), including CD127+ c-kit+ ST2L ILC3s, that expressed NKp44 and RORγt (fig. S12, A and B). Human ILC3s expressed MHCII [human leukocyte antigen-D related (HLA-DR)] in intestinal biopsies from non-IBD controls, whereas MHCII expression was largely absent on other ILC subsets (Fig. 4B). Although no alterations in the total frequency of ILC3s were observed between patient cohorts (fig. S12C), MHCII expression was significantly reduced on ILC3s (Fig. 4, C to E), but not CD4+ T cells or professional antigen-presenting cells (fig. S12, D and E), from pediatric Crohn’s disease patients in comparison to non-IBD controls. Moreover, we observed an inverse correlation between MHCII levels on ILC3s and frequencies of effector T helper 17 (TH17) cells in the colon (Fig. 4F) and circulating commensal bacteria–specific immunoglobulin G (IgG) titers (Fig. 4G) in pediatric Crohn’s disease patients. Taken together, these data indicate that alterations in MHCII on human ILC3s are associated with proinflammatory adaptive immune cell responses to commensal bacteria.

Fig. 4 ILC3-intrinsic MHCII is dysregulated in pediatric Crohn’s disease patients and is associated with increased intestinal TH17 cells.

(A) Lamina propria cells were isolated from colon biopsies from non-IBD control patients, and ILCs were identified as CD45+ and lineage (x axis: CD3, CD5, CD14, and FcεRI; y axis: CD11b, CD11c, and CD19) negative, CD127+, and further divided by expression of ST2L (ILC2s, red) and c-kit (ILC3s, blue) or as lacking expression of both markers (ILC1s, black). Expression of MHC class II (HLA-DR) was determined on ILC subsets in representative biopsies from (B) non-IBD patients or (C) pediatric Crohn’s disease (CD) patients, and the (D) frequencies and (E) MFI of HLA-DR expression on ILC3s was quantified. ILC3 HLA-DR MFI was correlated with (F) frequencies of IL-17A+ CD4+ TH17 cells in colon biopsies, and (G) commensal bacterial–specific IgG was quantified in the sera of pediatric Crohn’s disease patients. [(B) to (E)] Representative of n = 31 non-IBD and n = 31 CD patients or (F) n = 27 and (G) n = 21 pediatric Crohn’s disease patients. Results are shown as the mean ± SEM. Statistical analyses between patient groups were performed using a Mann-Whitney test. *P < 0.05; **P < 0.01; ***P < 0.001. Correlative analyses were compared by parametric Pearson’s rank correlation coefficient (r).

The mammalian gastrointestinal tract is colonized with trillions of beneficial commensal bacteria that regulate host nutrient metabolism and immune cell homeostasis and protect from pathogen infection (7, 11, 15). As such, commensal bacteria are an essential component of the mammalian “superorganism” required for the host to thrive (41). It is well characterized that self-specific CD4+ T cells with the potential to cause pathologic inflammation in mammalian tissues are controlled through antigen-dependent thymic selection (15). Here, MHCII-expressing CCR6+ ILC3s were found to control intestinal homeostasis through induction of apoptotic cell death and deletion of activated commensal bacteria–specific T cells, a process with multiple similarities to negative selection in the thymus, which we propose to term intestinal selection (fig. S13). Thus, intestinal selection controls the peripheral commensal bacteria–specific CD4+ T cell pool in concert with other previously described tolerogenic pathways, including Treg, production of IgA, and active maintenance of intestinal barrier function (7, 15, 17, 23). Dysregulated ILC3-intrinsic MHCII in pediatric Crohn’s disease patients suggests a possible role for alterations in this pathway in the onset and/or progression of human IBD. Thus, MHCII+ ILC3 may represent a novel therapeutic target to control pathologic CD4+ T cell responses in chronic human inflammatory disorders associated with dysregulated host-commensal bacteria relationships (7, 10, 15).

Supplementary Materials

www.sciencemag.org/content/348/6238/1031/suppl/DC1

Materials and Methods

Figs. S1 to S13

References (4246)

References and Notes

  1. Acknowledgments: The authors thank members of the Sonnenberg laboratory for discussions and critical reading of the manuscript. We thank C. Hunter and S. Wagage (University of Pennsylvania) for the Ahr-deficient mice; I. Brodsky (University of Pennsylvania) for the Caspase 1/11-deficient mice; and M. Jenkins, J. Walter, and T. Dileepan (University of Minnesota) for tetramer reagents and protocols. Data presented in this manuscript are tabulated in the main paper and in the supplementary materials. Microarray data are accessible at Gene Expression Omnibus (www.ncbi.nlm.nih.gov/geo) via accession number GSE67076. CBir1 Tg mice are available from University of Alabama, Rorc(γt)-GfpTG and RorcCre mice are available from Institut Pasteur, STAT5-CA mice are available from University of Minnesota, IAbbSTOPfl/fl mice and CD11c Tg mice are available from University of Pennsylvania, and Il23a deficient mice are available from Janssen Research and Development LLC, all under Material Transfer Agreement. Research in the Sonnenberg laboratory is supported by the National Institutes of Health (DP5OD012116), the National Institute of Allergy and Infectious Diseases Mucosal Immunology Studies Team (MIST) Scholar Award in Mucosal Immunity, and the Institute for Translational Medicine and Therapeutics Transdisciplinary Program in Translational Medicine and Therapeutics (UL1-RR024134 from the U.S. National Center for Research Resources). M.R.H. is supported by a research fellowship from the Crohn’s and Colitis Foundation of America (CCFA, no. 297365). T.C.F. is supported by a Cancer Research Institute Student Training and Research in Tumor immunology (STaRT) grant. D.R.W. is supported by a Wellcome Trust Research Career Development Fellowship. C.O.E. is supported by the National Institutes of Health (DK071176).
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