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.

白细胞介素-2（Interleukin-2, IL-2）是一种多效性细胞因子，对预防胃肠道慢性炎症至关重要。IL-2的保护效应涉及调节性T细胞（regulatory T cells, Tregs）的生成、维持与功能发挥，而低剂量IL-2已成为炎症性肠病（inflammatory bowel disease, IBD）患者的潜在治疗策略。然而，在肠道生理稳态下调控IL-2产生的细胞与分子通路仍未明确。本研究证实，IL-2是维持全胃肠道调节性T细胞稳态与免疫稳态的必需因子。值得注意的是，T细胞中IL-2的谱系特异性敲除可在大肠中重现上述表型，但无法在小肠中复制该效应。无偏分析显示，第三组固有淋巴样细胞（group 3 innate lymphoid cells, ILC3）是小肠中IL-2的主要细胞来源，其IL-2的产生受IL-1β选择性诱导。巨噬细胞在小肠中分泌IL-1β，该通路的激活依赖于MyD88与Nod2介导的微生物群感知。功能丧失实验证实，ILC3来源的IL-2是特异性维持小肠内调节性T细胞稳态、免疫稳态及膳食抗原口服耐受的关键因子。进一步研究发现，克罗恩病患者的小肠组织中，ILC3产生IL-2的能力显著降低，且这一现象与调节性T细胞数量减少密切相关。综上，本研究揭示了一条此前未被报道的通路：依赖于微生物群与IL-1β的信号轴可促进ILC3产生IL-2，从而调控小肠的免疫平衡。实验整体设计：分别从3只野生型小鼠中，分选得到CD45+CD3-RORγtGFP+CD127+的ILC3与CD45+CD3+CD4+的CD4+ T细胞，并提取其RNA。