Abstract
The intestinal microbiota modulates IL-22 production in the intestine, including the induction of IL-22-producing CD4+ T helper cells. Which specific bacteria are responsible for the induction of these cells is less well understood. Here, we demonstrate through the use of novel gnotobiotic knock-in reporter mice that segmented filamentous bacteria (SFB), which are known for their ability to induce Th17 cells, also induce distinct IL-17A negative CD4+ T cell populations in the intestine. A subset of these cells instead produces IL-22 upon restimulation ex vivo and also during enteric infections. Furthermore, they produce a distinct set of cytokines compared to Th17 cells including the differential expression of IL-17F and IFN-γ. Importantly, genetic models demonstrate that these cells, presumably Th22 cells, develop independently of intestinal Th17 cells. Together, our data identifies that besides Th17, SFB also induces CD4+ T cell populations, which serve as immediate source of IL-22 during intestinal inflammation.
Highlights
Antigen-specific CD4+ T cells play pivotal roles during immune responses differentiating into diverse subsets of T helper (Th) cells
Leukocytes from the intestinal lamina propria (LPL) and lymphoid organs were isolated from conventionally housed IL-17AGFP IL-22BFP Foxp3RFP mice left uninfected and 1 day post infection (p. i.) with S. typhimurium (S. tm.) (Supplementary Figure S1A; gating strategy Supplementary Figure S1B)
Since we identified IFN-g expression from IL-17A+IL-22+ and IL-17A+IL-22+ CD4+ T cells using gene expression analysis, we aimed to analyze whether all segmented filamentous bacteria (SFB)-induced Th17 cells coproduce IFN-g or whether this is potentially specific for certain subpopulations during bystander activation after Salmonella infection
Summary
Antigen-specific CD4+ T cells play pivotal roles during immune responses differentiating into diverse subsets of T helper (Th) cells. These secrete potent immunoregulatory cytokines and form long-lasting memory. Th17 and Th22 are two subsets of CD4+ T cells that are considered crucial for maintaining the balance between homeostasis and inflammation at mucosal sites. Th17 cells are characterized by their production of effector cytokines interleukin (IL)-17A, IL-17F, and IL-22, thereby functioning as important activators of innate immune effectors and contributing to the mucosal defense against extracellular bacteria and fungi [1, 2]. As the effector molecule IL-22 confers both proinflammatory and/or tissue protective functions
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