Novel antigen-presenting cell imparts T reg -dependent tolerance to gut microbiota.

Autor: Akagbosu B; Immuno-Oncology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA., Tayyebi Z; Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Tri-Institutional Program in Computational Biology and Medicine, Weill Cornell Graduate School, New York, NY, USA., Shibu G; Immuno-Oncology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA.; Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine Graduate School of Medical Sciences, New York, NY, USA., Paucar Iza YA; Immuno-Oncology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA.; Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine Graduate School of Medical Sciences, New York, NY, USA., Deep D; Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine Graduate School of Medical Sciences, New York, NY, USA.; Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Tri-Institutional MD-PhD Program, Weill Cornell Medicine, The Rockefeller University and Memorial Sloan Kettering Cancer Center, New York, NY, USA., Parisotto YF; Immuno-Oncology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA., Fisher L; Immuno-Oncology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA.; Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine Graduate School of Medical Sciences, New York, NY, USA., Pasolli HA; Electron Microscopy Resource Center, The Rockefeller University, New York, NY, USA., Thevin V; Tumor Escape Resistance Immunity Department, CRCL, INSERM U1052, CNRS 5286, Centre Léon Bérard, Université de Lyon, Lyon, France.; Equipe Labellisée Ligue Nationale contre le Cancer, Lyon, France., Elmentaite R; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK., Knott M; Institute of PathologyFaculty of Medicine, LMU Munich, Munich, Germany., Hemmers S; Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine Graduate School of Medical Sciences, New York, NY, USA.; Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Immunology, Duke University, Durham, NC, USA., Jahn L; Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Friedrich C; Würzburg Institute of Systems Immunology, Max Planck Research Group, Julius-Maximilians-Universität Würzburg, Würzburg, Germany., Verter J; Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA., Wang ZM; Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA., van den Brink M; Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine Graduate School of Medical Sciences, New York, NY, USA.; Department of Immunology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Gasteiger G; Würzburg Institute of Systems Immunology, Max Planck Research Group, Julius-Maximilians-Universität Würzburg, Würzburg, Germany., Grünewald TGP; Hopp-Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.; Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany., Marie JC; Tumor Escape Resistance Immunity Department, CRCL, INSERM U1052, CNRS 5286, Centre Léon Bérard, Université de Lyon, Lyon, France.; Equipe Labellisée Ligue Nationale contre le Cancer, Lyon, France., Leslie C; Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Rudensky AY; Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine Graduate School of Medical Sciences, New York, NY, USA. rudenska@mskcc.org.; Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY, USA. rudenska@mskcc.org., Brown CC; Immuno-Oncology, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA. brownc10@mskcc.org.; Immunology and Microbial Pathogenesis Program, Weill Cornell Medicine Graduate School of Medical Sciences, New York, NY, USA. brownc10@mskcc.org.; Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. brownc10@mskcc.org.; Parker Institute for Cancer Immunotherapy, Memorial Sloan Kettering Cancer Center, New York, NY, USA. brownc10@mskcc.org.
Jazyk: angličtina
Zdroj: Nature [Nature] 2022 Oct; Vol. 610 (7933), pp. 752-760. Date of Electronic Publication: 2022 Sep 07.
DOI: 10.1038/s41586-022-05309-5
Abstrakt: Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (AIRE) have a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (T reg ) cell development 1-4 . Within weeks of birth, a separate wave of T reg cell differentiation occurs in the periphery upon exposure to antigens derived from the diet and commensal microbiota 5-8 , yet the cell types responsible for the generation of peripheral T reg (pT reg ) cells have not been identified. Here we describe the identification of a class of RORγt + antigen-presenting cells called Thetis cells, with transcriptional features of both mTECs and dendritic cells, comprising four major sub-groups (TC I-TC IV). We uncover a developmental wave of Thetis cells within intestinal lymph nodes during a critical window in early life, coinciding with the wave of pT reg cell differentiation. Whereas TC I and TC III expressed the signature mTEC nuclear factor AIRE, TC IV lacked AIRE expression and was enriched for molecules required for pT reg generation, including the TGF-β-activating integrin αvβ8. Loss of either major histocompatibility complex class II (MHCII) or ITGB8 by Thetis cells led to a profound impairment in intestinal pT reg differentiation, with ensuing colitis. By contrast, MHCII expression by RORγt + group 3 innate lymphoid cells (ILC3) and classical dendritic cells was neither sufficient nor required for pT reg generation, further implicating TC IV as the tolerogenic RORγt + antigen-presenting cell with an essential function in early life. Our studies reveal parallel pathways for the establishment of tolerance to self and foreign antigens in the thymus and periphery, respectively, marked by the involvement of shared cellular and transcriptional programmes.
(© 2022. The Author(s).)
Databáze: MEDLINE
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