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.

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Zhou L, Chu C, Teng F, Bessman NJ, Goc J, Santosa EK, Putzel GG, Kabata H, Kelsen JR, Baldassano RN, Shah MA, Sockolow RE, Vivier E, Eberl G, Smith KA, Sonnenberg GF