総説・解説等

＜文献概要＞慢性咳嗽のうち,好酸球性炎症を伴う咳嗽(咳喘息,アトピー咳嗽,非喘息性好酸球性気管支炎)が半数以上を占めている。従来,好酸球性炎症はTh2細胞から産生される2型サイトカイン(interleukin[IL]-4やIL-5,IL-13など)によって引き起こされると考えられていたが,最近ではグループ2自然リンパ球(ILC2)も好酸球性炎症に寄与していると考えられている。特に,ウイルス感染後の好酸球性炎症にはILC2が関与し,気道におけるIL-33やthymic stromal lymphopoietin(TSLP),interferon(IFN)などの産生量によって,ILC2を介した好酸球性炎症が慢性化することが示唆されている。

© 2019, The Author(s), under exclusive licence to Springer Nature Limited. 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 (T reg ) 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 T reg cells and immunological homeostasis throughout the gastrointestinal tract. Notably, lineage-specific deletion of IL-2 in T cells did not reduce T reg 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-1β. Macrophages in the small intestine produce IL-1β, 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 T reg 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 T reg cells. Our results reveal a previously unappreciated pathway in which a microbiota- and IL-1β-dependent axis promotes the production of IL-2 by ILC3s to orchestrate immune regulation in the intestine.