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(1-4). The protective effects of IL-2 involve the generation, maintenance and function of regulatory T (Treg) cells(4-8), and the use of low doses of IL-2 has emerged as a potential therapeutic strategy for patients with inflammatory bowel disease(9). However, the cellular and molecular pathways that control the production of IL-2 in the context of intestinal health are undefined. Here we show, in a mouse model, that IL-2 is acutely required to maintain Treg cells and immunological homeostasis throughout the gastrointestinal tract. Notably, lineage-specific deletion of IL-2 in T cells did not reduce Treg cells in the small intestine. Unbiased analyses revealed that, in the small intestine, group-3 innate lymphoid cells (ILC3s) are the dominant cellular source of IL-2, which is induced selectively by IL-1 beta. Macrophages in the small intestine produce IL-1 beta, and activation of this pathway involves MYD88-and NOD2-dependent sensing of the microbiota. Our loss-of-function studies show that ILC3-derived IL-2 is essential for maintaining Treg cells, immunological homeostasis and oral tolerance to dietary antigens in the small intestine. Furthermore, production of IL-2 by ILC3s was significantly reduced in the small intestine of patients with Crohn's disease, and this correlated with lower frequencies of Treg cells. Our results reveal a previously unappreciated pathway in which a microbiota-and IL-1 beta-dependent axis promotes the production of IL-2 by ILC3s to orchestrate immune regulation in the intestine.