GSE126580
Innate lymphoid cells support regulatory T cells in the intestine through interleukin-2
Interleukin (IL)-2 is a pleiotropic cytokine that is necessary to prevent chronic inflammation in the gastrointestinal tract.  The protective effects of IL-2 involve the generation, maintenance and function of regulatory T cells (Tregs), and low-dose IL-2 has emerged as a potential therapeutic strategy in inflammatory bowel disease (IBD) patients.  However, the cellular and molecular pathways that control the production of IL-2 in the context of intestinal health are undefined.  Here we identify that IL-2 is acutely required to maintain Tregs and immunologic homeostasis throughout the gastrointestinal tract.  Strikingly, lineage-specific deletion of IL-2 in T cells could recapitulate these phenotypes in the large intestine, but not in the small intestine.  Unbiased analyses revealed that group 3 innate lymphoid cells (ILC3) are the dominant cellular source of IL-2 in the small intestine, which is selectively induced by IL-1ß.  Macrophages produce IL-1ß in the small intestine and activation of this pathway involves MyD88- and Nod2-dependent sensing of the microbiota.  Loss-of-function studies defined that ILC3-derived IL-2 is essential to maintain Tregs, immunologic homeostasis and oral tolerance to dietary antigens uniquely in the small intestine.  Furthermore, ILC3 production of IL-2 was significantly reduced in the small intestine of Crohn's disease patients, and this correlated with diminished Tregs.  Collectively, these results reveal a previously unappreciated pathway whereby a microbiota- and IL-1ß-dependent axis promotes ILC3 production of IL-2 to orchestrate immune regulation in the small intestine. Overall design: RNAs of ILC3s or CD4+ T cells were respectively sorted as CD45+CD3-ROR?tGFP+CD127+ or CD45+CD3+CD4+ from 3 wild type mice.