Interleukin-22 (IL-22) is central to host protection against bacterial infections at barrier sites. Both innate lymphoid cells (ILCs) and T cells produce IL-22. However, the specific contributions of ...CD4+ T cells and their developmental origins are unclear. We found that the enteric pathogen Citrobacter rodentium induced sequential waves of IL-22-producing ILCs and CD4+ T cells that were each critical to host defense during a primary infection. Whereas IL-22 production by ILCs was strictly IL-23 dependent, development of IL-22-producing CD4+ T cells occurred via an IL-6-dependent mechanism that was augmented by, but not dependent on, IL-23 and was dependent on both transcription factors T-bet and AhR. Transfer of CD4+ T cells differentiated with IL-6 in the absence of TGF-β (“Th22” cells) conferred complete protection of infected IL-22-deficient mice whereas transferred Th17 cells did not. These findings establish Th22 cells as an important component of mucosal antimicrobial host defense.
► IL-23-deficient mice are protected from low-dose Citrobacter rodentium infection ► CD4+ T cell-derived IL-22 is required for C. rodentium infection protection ► Th22 cells provide more effective antibacterial defense than do Th17 cells ► T-bet acts cooperatively with AhR in Il22 induction in Th22 cells
The emergence of the adaptive immune system in vertebrates set the stage for evolution of an advanced symbiotic relationship with the intestinal microbiota. The defining features of specificity and ...memory that characterize adaptive immunity have afforded vertebrates the mechanisms for efficiently tailoring immune responses to diverse types of microbes, whether to promote mutualism or host defence. These same attributes can put the host at risk of immune-mediated diseases that are increasingly linked to the intestinal microbiota. Understanding how the adaptive immune system copes with the remarkable number and diversity of microbes that colonize the digestive tract, and how the system integrates with more primitive innate immune mechanisms to maintain immune homeostasis, holds considerable promise for new approaches to modulate immune networks to treat and prevent disease.
Summary
Discovery of the T‐helper 17 (Th17) subset heralded a major shift in T‐cell biology and immune regulation. In addition to defining a new arm of the adaptive immune response, studies of the ...Th17 pathway have led to a greater appreciation of the developmental flexibility, or plasticity, that is a feature of T‐cell developmental programs. Since the initial finding that differentiation of Th17 cells is promoted by transforming growth factor‐β (TGFβ), it became clear that Th17 cell development overlapped that of induced regulatory T (iTreg) cells. Subsequent findings established that Th17 cells are also unusually flexible in their late developmental programming, demonstrating substantial overlap with conventional Th1 cells through mechanisms that are just beginning to be understood but would appear to have important implications for immunoregulation at homeostasis and in immune‐mediated diseases. Herein we examine the developmental and functional features of Th17 cells in relation to iTreg cells, Th1 cells, and Th22 cells, as a basis for understanding the contributions of this pathway to host defense, immune homeostasis, and immune‐mediated disease.
Th17 cells reactive to the enteric microbiota are central to the pathogenesis of certain types of inflammatory bowel disease. However, Th17 cells display substantial developmental plasticity, such ...that some progeny of Th17 cell precursors retain a predominantly IL-17A ⁺ phenotype, whereas others extinguish IL-17 expression and acquire expression of IFN-γ, giving rise to “Th1-like” cells. It remains unclear what role these subsets play in inflammatory bowel disease. Using a Th17 transfer model of colitis, we found that IFN-γ–deficient Th17 cells retained an IL-17A ⁺ phenotype and were unable to induce colitis in recipients. Development of disease required the transition of a subset of Th17 precursors to Th1-like cells and was contingent on the expression of both Stat4 and T-bet, but not the IL-12 or IFN-γ receptors. Moreover, Th17 cells could provide “help” for the development of pathogenic Th1 cells from naïve precursors. These results indicate that Th17 cells are potent mediators of colitis pathogenesis by dual mechanisms: by directly transitioning to Th1-like cells and by supporting the development of classic Th1 cells.
Significance The Th17 subset of CD4 ⁺ T cells are important in the pathogenesis of inflammatory bowel disease (IBD), but the mechanisms of their actions, particularly the role of the development of IFN-γ–producing progeny of Th17 cells (Th1-like cells), are incompletely understood. Here, we show in a mouse model of Th17-driven IBD that transition of Th17 precursors to Th1-like cells is absolutely required for disease, because Th17 cells deficient in IFN-γ fail to induce intestinal inflammation. This transition is dependent on the transcription factors T-bet and, to a lesser extent, Stat4. These findings are relevant for clinical strategies that target IBD and suggest that focusing on both the Th17 and Th1-like arms of disease may be beneficial in therapy design.
T helper 17 (Th17) cells can give rise to interleukin-17A (IL-17A)- and interferon (IFN)-γ-double-producing cells that are implicated in development of autoimmune diseases. However, the molecular ...mechanisms that govern generation of IFN-γ-producing Th17 cells are unclear. We found that coexpression of the Th1 and Th17 cell master transcription factors, T-bet and retinoid-related orphan receptor gamma-t (RORγt), respectively, did not generate Th cells with robust IL-17 and IFN-γ expression. Instead, development of IFN-γ-producing Th17 cells required T-bet and Runx1 or Runx3. IL-12-stimulated Th17 cells upregulated Runx1, which bound to the Ifng locus in a T-bet-dependent manner. Reciprocally, T-bet or Runx1 deficiency or inhibition of Runx transcriptional activity impaired the development of IFN-γ-producing Th17 cells during experimental autoimmune encephalomyelitis, which correlated with substantially ameliorated disease course. Thus, our studies identify a critical role for T-bet and Runx transcription factors in the generation of pathogenic IFN-γ-producing Th17 cells.
•T-bet and RORγt coexpression does not generate Th1-like Th17 cells•T-bet and Runx transcription factors regulate Th1-like Th17 cell differentiation•Runx1 binds to Ifng locus in a T-bet-dependent manner in IL-12-stimulated Th17 cells•Generation of Th1-like Th17 cells in vivo is impaired in the absence of Runx1 or Runx3
IL-22 plays an important role in mucosal epithelial cell homeostasis. Using a dextran sodium sulfate-induced mouse model of acute colitis, we observed an IL-23-dependent up-regulation of IL-22 in the ...middle and distal colon at the onset of epithelial cell damage. This heightened IL-22 correlated with an influx of innate immune cells, suggesting an important role in colonie epithelial protection. Freshly isolated colon-infiltrating neutrophils produced IL-22 contingent upon IL-23 signaling, and IL-22 production was augmented by TNFa. Importantly, the depletion of neutrophils resulted in diminished IL-22 levels in the colon, and the transfer of IL-22-competent neutrophils to IL-22a-deficient mice protected the colonie epithelium from dextran sodium sulfate-induced damage. In addition, IL-22-producing neutrophils targeted colonie epithelial cells to up-regulate the antimicrobial peptides, Reglllp and S100A8. This study establishes a role for neutrophils in providing IL-22-dependent mucosal epithelial support that contributes to the resolution of colitis.
The recent discovery of a new CD4+ T cell subset, Th17, has transformed our understanding of the pathogenetic basis of an increasing number of chronic immune-mediated diseases. Particularly in ...tissues that interface with the microbial environment-such as the intestinal and respiratory tracts and the skin-where most of the Th17 cells in the body reside, dysregulated immunity to self (or the extended self, the diverse microbiota that normally colonize these tissues) can result in chronic inflammatory disease. In this review, we focus on recent advances in the biology of the Th17 pathway and on genome-wide association studies that implicate this immune pathway in human disease involving these tissues.
Two models are proposed to explain Notch function during helper T (Th) cell differentiation. One argues that Notch instructs one Th cell fate over the other, whereas the other posits that Notch ...function is dictated by cytokines. Here we provide a detailed mechanistic study investigating the role of Notch in orchestrating Th cell differentiation. Notch neither instructed Th cell differentiation nor did cytokines direct Notch activity, but instead, Notch simultaneously regulated the Th1, Th2, and Th17 cell genetic programs independently of cytokine signals. In addition to regulating these programs in both polarized and nonpolarized Th cells, we identified Ifng as a direct Notch target. Notch bound the Ifng CNS-22 enhancer, where it synergized with Tbet at the promoter. Thus, Notch acts as an unbiased amplifier of Th cell differentiation. Our data provide a paradigm for Notch in hematopoiesis, with Notch simultaneously orchestrating multiple lineage programs, rather than restricting alternate outcomes.
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•Notch concurrently regulates Th1, Th2, and Th17 cell differentiation•Notch activity is unbiased and is not affected by the cytokine environment•Notch regulates Ifng at the Ifng CNS-22 and synergizes with Tbet at the promoter•Notch can simultaneously orchestrate multiple lineage programs
The interleukin-17 (IL-17) family of cytokines phylogenetically predates the evolution of T cells in jawed vertebrates, suggesting that the ontogeny of the Th17 cell lineage must have arisen to ...confer an evolutionary advantage to the host over innate sources of IL-17. Utilizing a model of mucosal immunization with the encapsulated bacteria
Klebsiella pneumoniae, we found that B cells, which largely recognized polysaccharide capsular antigens, afforded protection to only the vaccine strain. In contrast, memory Th17 cells proliferated in response to conserved outer membrane proteins and conferred protection against several serotypes of
K. pneumoniae, including the recently described multidrug resistant New Dehli metallolactamase strain. Notably, this heterologous, clade-specific protection was antibody independent, demonstrating the Th17 cell lineage confers a host advantage by providing heterologous mucosal immunity independent of serotype-specific antibody.
► Th17 cells generated by vaccination confer cross-serotype protection ► Memory Th17 cells mediate direct protection in an antigen-specific manner ► Th17 cells protect against multidrug resistant
Klebsiella challenge
Th17 cells have emerged as important mediators of host defense and homeostasis at barrier sites, particularly the intestines, where the greatest number and diversity of the microbiota reside. A ...critical balance exists between protection of the host from its own microbiota and pathogens and the development of immune-mediated disease. Breaches of local innate immune defenses provide critical stimuli for the induction of Th17 cell development, and additional cues within these tissues promote Th17 cell survival and/or plasticity. Normally, this results in eradication of the microbial threat and restitution of homeostasis. When dysregulated, however, Th17 cells can cause a range of immune-mediated diseases, whether directed against Ags derived from the microbiota, such as in inflammatory bowel disease, or against self-Ags in a range of autoimmune diseases. This review highlights recent discoveries that provide new insights into ways in which environmental signals impact Th17 cell development and function in the intestines.
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