Innate lymphoid cells support regulatory T cells in the intestine through interleukin-2

Abstract

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 cells (Tregs) 4 – 8 , and low-dose IL-2 has emerged as a potential therapeutic strategy in inflammatory bowel disease (IBD) patients 9 . 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 did not recapitulate these phenotypes 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-1β. Macrophages produce IL-1β 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-1β-dependent axis promotes ILC3 production of IL-2 to orchestrate immune regulation in the intestine.

Human Intestinal Mononuclear Phagocytes in Health and Inflammatory Bowel Disease

“…Finally, Fenton et al showed that the frequency of αVβ8 + cDC2, which are thought to induce Tregs, doubled in Crohn's patients compared to controls (266). However, intestinal Treg frequency among CD4 + T cells decreased in Crohn's patients (306). Nevertheless, given recent evidence that enhancing the ability of intestinal T cells to sense active TGFβ is effective in inducing remission in some Crohn's patients (307), boosting the αVβ8-TGF-β pathway may be an attractive complementary therapeutic approach to weaken inflammatory T cell responses (266).…”

The interaction of intestinal microbiota and innate lymphoid cells in health and disease throughout life

“…Moreover, upregulation of apoptotic signals has been reported in ILC3s induced by plasmacytoid dendritic cell (pDC)‐derived interferon upon HIV in humanized mice. Microbiota triggered IL‐2 production by ILC3 has just recently been shown to support Tregs . It is tempting to speculate that loss of IL‐2 producing ILC populations may have a direct effect on T‐cell homeostasis in HIV infection.…”

“…Microbiota triggered IL-2 production by ILC3 has just recently been shown to support Tregs. 142 It is tempting to speculate that loss of IL-2 producing ILC populations may have a direct effect on T-cell homeostasis in HIV infection.…”

The balance of power: innate lymphoid cells in tissue inflammation and repair

“…In addition, induction of ILC3-derived IL-22 by adherent microbiota triggers epithelial cell regulation of IL-17 production by intestinal T cells (54). Under homeostatic conditions, commensal microbiota and IL-1β also stimulate ILC3 production of GM-CSF as well as IL-2, which act via nonredundant pathways to promote intestinal Tregs (137,138). Antigen processing and presentation by MHC II + ILC3s provide a mechanism for antigen-specific regulation of commensal-specific T cells (139).…”

“…While IL-1β can trigger splenic ILC3 expression of CD80 and CD86 to support T cell activation (140), the absence of these costimulatory molecules on intestinal ILC3s limits homeostatic T cell activation (141). Under an inflammatory microenvironment such as IBD, these regulatory mechanisms are reduced (138,141). Moreover, increased TL1A, which is highly expressed by MNPs in IBD, can induce robust expression of the costimulatory molecule OX40L on MHC II + ILC3s and drive colonic T cell-dependent inflammation (85).…”