Distinct RORγt-dependent Th17 immune responses are required for autoimmune pathogenesis and protection against bacterial infection.

IF 7.5 1区 生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2024-11-05 DOI:10.1016/j.celrep.2024.114951
Xiancai Zhong, Hongmin Wu, Wencan Zhang, Yun Shi, Yousang Gwack, Hai-Hui Xue, Zuoming Sun
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Abstract

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.

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自身免疫发病机制和抵御细菌感染需要不同的 RORγt 依赖性 Th17 免疫反应。
T辅助(Th)17细胞介导保护性抗菌免疫反应和自身免疫发病机制,但调节这些Th17反应的不同途径仍不清楚。视黄酸相关孤儿受体γ t(RORγt)是一种主转录因子,它控制着Th17细胞的生成和效应功能。我们发现,RORγt中的K256R突变会损害Th17介导的实验性自身免疫性脑脊髓炎(EAE),但不会影响棒状杆菌的清除。这表明 RORγt 在中枢神经系统发病机制与肠道相关的 Th17 保护性反应中发挥着不同的作用。从机理上讲,RORγt/Runx1依赖性上调CD4+ T细胞中的galectin-3(Lgals3)和趋化因子受体Ccr6对EAE的发生至关重要,但对细菌的清除却并非如此。此外,Lgals3 是招募巨噬细胞产生白细胞介素(IL)-1β的选择性必需因子,而白细胞介素-1β又会在 EAE 发病过程中促进 CD4+ T 细胞上的 Ccr6 表达。我们的发现强调了自身免疫和抗菌免疫中不同的RORγ调控Th17通路,这对针对Th17介导的自身免疫同时保留有效的抗菌反应的疗法具有重要意义。
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来源期刊
Cell reports
Cell reports CELL BIOLOGY-
CiteScore
13.80
自引率
1.10%
发文量
1305
审稿时长
77 days
期刊介绍: Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.
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