Tissue-resident commensal TH17 cells possess regulatory functions

Commensal microbes induce cytokine-producing effector tissue-resident CD4 T cells, but the function of these T cells in mucosal homeostasis is not well understood. Here we report that commensal-specific intestinal TH17 cells possess an anti-inflammatory phenotype marked by expression of IL-10 and co-inhibitory receptors. The anti-inflammatory phenotype of gut-resident commensal-specific TH17 cells was driven by the transcription factor c-MAF. IL-10-producing commensal-specific TH17 cells were heterogeneous and derived from a TCF1+ gut-resident progenitor TH17 cell population. TH17 cells acquired IL-10 expression and anti-inflammatory phenotype in the small intestinal lamina propria. IL-10-production by CD4 T cells and IL-10 signaling in intestinal macrophages drove IL-10 expression by commensal-specific TH17 cells. Intestinal commensal-specific TH17 cells possessed immunoregulatory functions and curbed effector T cell activity in vitro and in vivo in an IL-10-dependent and c-MAF-dependent manner. Our results suggest that tissue-resident commensal-specific TH17 cells perform regulatory functions in mucosal homeostasis.