c-Maf 抑制 T-bet 驱动的 CCR6-阴性组 3 固有淋巴细胞的编程。
c-Maf restrains T-bet-driven programming of CCR6-negative group 3 innate lymphoid cells.
机构信息
Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, Berlin, Germany.
出版信息
Elife. 2020 Feb 10;9:e52549. doi: 10.7554/eLife.52549.
RORγt group 3 innate lymphoid cells (ILC3s) maintain intestinal homeostasis through secretion of type 3 cytokines such as interleukin (IL)-17 and IL-22. However, CCR6 ILC3s additionally co-express T-bet allowing for the acquisition of type 1 effector functions. While T-bet controls the type 1 programming of ILC3s, the molecular mechanisms governing T-bet are undefined. Here, we identify c-Maf as a crucial negative regulator of murine T-bet CCR6 ILC3s. Phenotypic and transcriptomic profiling of c-Maf-deficient CCR6 ILC3s revealed a hyper type 1 differentiation status, characterized by overexpression of ILC1/NK cell-related genes and downregulation of type 3 signature genes. On the molecular level, c-Maf directly restrained T-bet expression. Conversely, c-Maf expression was dependent on T-bet and regulated by IL-1β, IL-18 and Notch signals. Thus, we define c-Maf as a crucial cell-intrinsic brake in the type 1 effector acquisition which forms a negative feedback loop with T-bet to preserve the identity of CCR6 ILC3s.
RORγt 组 3 固有淋巴细胞 (ILC3s) 通过分泌 3 型细胞因子（如白细胞介素 [IL]-17 和 IL-22）来维持肠道内稳态。然而，CCR6 ILC3s 还共同表达 T-bet，使其获得 1 型效应功能。虽然 T-bet 控制 ILC3s 的 1 型编程，但调控 T-bet 的分子机制尚不清楚。在这里，我们发现 c-Maf 是控制小鼠 T-bet CCR6 ILC3s 的关键负调控因子。c-Maf 缺陷型 CCR6 ILC3s 的表型和转录组分析显示出超 1 型分化状态，其特征是 ILC1/NK 细胞相关基因的过度表达和 3 型特征基因的下调。在分子水平上，c-Maf 直接抑制 T-bet 的表达。相反，c-Maf 的表达依赖于 T-bet，并受 IL-1β、IL-18 和 Notch 信号的调节。因此，我们将 c-Maf 定义为 1 型效应获得的关键细胞内制动器，它与 T-bet 形成负反馈回路，以维持 CCR6 ILC3s 的身份。
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