Department of Immunology & Theranostics, Arthur Riggs Diabetes and Metabolism Research Institute, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Department of Physiology, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095, USA.
Cell Rep. 2024 Nov 26;43(11):114951. doi: 10.1016/j.celrep.2024.114951. Epub 2024 Nov 5.
T helper (Th)17 cells mediate both protective anti-bacterial immune responses and autoimmune pathogenesis, but the distinct pathways regulating these Th17 responses remain unclear. Retinoid-related orphan receptor γ t (RORγt) is a master transcription factor that governs Th17 cell generation and effector functions. We found that a K256R mutation in RORγt impairs Th17-mediated experimental autoimmune encephalomyelitis (EAE) without affecting the clearance of Citrobacter rodentium. This indicates distinct RORγt roles in central nervous system pathogenesis versus gut-associated protective Th17 responses. Mechanically, RORγt/Runx1-dependent upregulation of galectin-3 (Lgals3) and chemokine receptor Ccr6 in CD4 T cells is essential for EAE development but not for bacterial clearance. Moreover, Lgals3 is selectively required for recruiting macrophages to produce interleukin (IL)-1β, which in turn promotes Ccr6 expression on CD4 T cells during EAE pathogenesis. Our findings highlight different RORγt-regulated Th17 pathways in autoimmunity and anti-bacterial immunity, with implications for therapies targeting Th17-mediated autoimmunity while preserving effective anti-bacterial responses.
辅助性 T 细胞 17（Th17）细胞介导保护性抗细菌免疫反应和自身免疫发病机制，但调节这些 Th17 反应的不同途径尚不清楚。维甲酸相关孤儿受体 γ t（RORγt）是一种主转录因子，可调控 Th17 细胞的生成和效应功能。我们发现 RORγt 中的 K256R 突变可损害 Th17 介导的实验性自身免疫性脑脊髓炎（EAE），而不影响鼠柠檬酸杆菌的清除。这表明 RORγt 在中枢神经系统发病机制与与肠道相关的保护性 Th17 反应中具有不同的作用。从机制上讲，RORγt/Runx1 依赖性上调 CD4 T 细胞中的半乳糖凝集素 3（Lgals3）和趋化因子受体 Ccr6 对于 EAE 的发展是必需的，但对于细菌清除则并非必需。此外，Lgals3 对于招募巨噬细胞产生白细胞介素（IL）-1β是选择性必需的，IL-1β反过来又促进 EAE 发病过程中 CD4 T 细胞上 Ccr6 的表达。我们的研究结果突出了自身免疫和抗细菌免疫中不同的 RORγt 调节的 Th17 途径，这对于针对 Th17 介导的自身免疫而保留有效抗细菌反应的治疗具有重要意义。
