{"title":"Distinct RORγt-dependent Th17 immune responses are required for autoimmune pathogenesis and protection against bacterial infection.","authors":"Xiancai Zhong, Hongmin Wu, Wencan Zhang, Yun Shi, Yousang Gwack, Hai-Hui Xue, Zuoming Sun","doi":"10.1016/j.celrep.2024.114951","DOIUrl":null,"url":null,"abstract":"<p><p>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<sup>+</sup> 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<sup>+</sup> 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.</p>","PeriodicalId":9798,"journal":{"name":"Cell reports","volume":"43 11","pages":"114951"},"PeriodicalIF":7.5000,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell reports","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.celrep.2024.114951","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
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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