ILC3s select for RORγt + Tregs and establish tolerance to intestinal microbiota
ILC3s select for RORγt + Tregs and establish tolerance to intestinal microbiota
Abstract Microbial colonization of the mammalian intestine elicits inflammatory or tolerogenic T cell responses, but the mechanisms controlling these distinct outcomes remain poorly understood and accumulating evidence indicates that aberrant immunity to intestinal microbiota is causally associated with infectious, inflammatory, and malignant diseases1–8. Here, we define a critical pathway controlling the fate of inflammatory versus tolerogenic T cells that are specific for the microbiota and express the transcription factor RORγt. We profiled all RORγt+ immune cells at single cell resolution from the intestine-draining lymph nodes of mice and reveal a dominant presence of Tregs and lymphoid tissue-induced (LTi)-like group 3 innate lymphoid cells (ILC3s), which co-localize at interfollicular regions. These ILC3s have interconverting potential with RORγt+ extrathymic Aire-expressing cells, abundantly express major histocompatibility complex class II, and are necessary and sufficient to promote microbiota-specific RORγt+ Tregs and prevent their expansion as inflammatory T helper (Th)17 cells. This occurs through ILC3-mediated antigen-presentation, interleukin-2 gradients, and αv integrin. Finally, single-cell analyses demonstrate that ILC3 and RORγt+ Treg interactions are impaired in inflammatory bowel disease. Our results define a novel paradigm whereby ILC3s positively select for antigen specific RORγt+ Tregs, and against Th17 cells, to establish immune tolerance to the microbiota and intestinal health.
Zhang Wen、Sonnenberg Gregory F.、Gaspal Fabrina、Fox James G.、Sockolow Robbyn E.、Live Cell Bank JRI、Laufer Terri M.、Zhou Wenqing、Lyu Mengze、Goc Jeremy、Fan Yong、Suzuki Hiroaki、Zhou Lei、Eberl Gerard、Shen Zeli、Zhou Jordan、Kang Lan、Withers David R.
Joan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, Cornell University||Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University||Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell UniversityJoan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, Cornell University||Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University||Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell UniversityInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamDivision of Comparative Medicine, Massachusetts Institute of TechnologyDepartment of Pediatrics, Division of Gastroenterology and Nutrition, Weill Cornell Medicine, Cornell UniversityJoan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, Cornell UniversityPerelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Philadelphia Veterans Affairs Medical CenterJoan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, Cornell University||Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University||Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell UniversityJoan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, Cornell University||Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University||Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell UniversityJoan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, Cornell University||Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University||Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell UniversityInstitute of Cellular Therapeutics, Allegheny Health NetworkJoan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, Cornell University||Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University||Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University||EA Pharma Co., LtdJoan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, Cornell University||Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University||Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell UniversityMicroenvironment & Immunity Unit, Institut PasteurDivision of Comparative Medicine, Massachusetts Institute of TechnologyJoan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, Cornell University||Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University||Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell UniversityJoan and Sanford I. Weill Department of Medicine, Division of Gastroenterology, Weill Cornell Medicine, Cornell University||Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University||Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell UniversityInstitute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham
基础医学微生物学
Zhang Wen,Sonnenberg Gregory F.,Gaspal Fabrina,Fox James G.,Sockolow Robbyn E.,Live Cell Bank JRI,Laufer Terri M.,Zhou Wenqing,Lyu Mengze,Goc Jeremy,Fan Yong,Suzuki Hiroaki,Zhou Lei,Eberl Gerard,Shen Zeli,Zhou Jordan,Kang Lan,Withers David R..ILC3s select for RORγt + Tregs and establish tolerance to intestinal microbiota[EB/OL].(2025-03-28)[2025-05-06].https://www.biorxiv.org/content/10.1101/2022.04.25.489463.点此复制
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