Innate lymphoid cells (ILCs) have a protective immune function at mucosal tissues but can also contribute to immunopathology. Previous work has shown that the serine/threonine kinase mammalian target of rapamycin complex 1 (mTORC1) is involved in generating protective ILC3 cytokine responses during bacterial infection. However, whether mTORC1 also regulates IFN-γ-mediated immunopathology has not been investigated. In addition, the role of mTORC2 in ILC3s is unknown. Using mice specifically defective for either mTORC1 or mTORC2 in ILC3s, we show that both mTOR complexes regulate the maintenance of ILC3s at steady state and pathological immune response during colitis. mTORC1 and to a lesser extend mTORC2 promote the proliferation of ILC3s in the small intestine. Upon activation, intestinal ILC3s produce less IFN-γ in the absence of mTOR signaling. During colitis, loss of both mTOR complexes in colonic ILC3s results in the reduced production of inflammatory mediators, recruitment of neutrophils and immunopathology. Similarly, treatment with rapamycin after colitis induction ameliorates the disease. Collectively, our data show a critical role for both mTOR complexes in controlling ILC3 cell numbers and ILC3-driven inflammation in the intestine.

先天性淋巴样细胞 (ILC) 在粘膜组织中具有保护性免疫功能，但也有助于免疫病理学。先前的研究表明，雷帕霉素复合物 1 (mTORC1) 的丝氨酸/苏氨酸激酶哺乳动物靶点参与在细菌感染期间产生保护性 ILC3 细胞因子反应。然而，mTORC1 是否也调节 IFN-γ 介导的免疫病理学尚未得到研究。此外，mTORC2 在 ILC3 中的作用尚不清楚。使用 ILC3 中 mTORC1 或 mTORC2 特异性缺陷的小鼠，我们表明这两种 mTOR 复合物均调节结肠炎期间 ILC3 处于稳态和病理免疫反应的维持。mTORC1 和较小程度的 mTORC2 促进小肠中 ILC3 的增殖。激活后，肠道 ILC3 在没有 mTOR 信号传导的情况下产生较少的 IFN-γ。在结肠炎期间，结肠 ILC3 中两种 mTOR 复合物的丢失导致炎症介质的产生减少、嗜中性粒细胞的募集和免疫病理学。同样，结肠炎诱导后用雷帕霉素治疗可改善疾病。总的来说，我们的数据显示了 mTOR 复合物在控制 ILC3 细胞数量和 ILC3 驱动的肠道炎症方面的关键作用。