BACH2 regulates diversification of regulatory and proinflammatory chromatin states in T H 17 cells.

Autor: Thakore PI; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Genentech, South San Francisco, CA, USA., Schnell A; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Whitehead Institute for Biomedical Research, Cambridge, MA, USA., Huang L; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Department of Data Sciences, Dana-Farber Cancer Institute, Boston, MA, USA.; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, USA., Zhao M; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Hou Y; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Christian E; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Zaghouani S; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Wang C; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Department of Immunology, University of Toronto and Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Ontario, Canada., Singh V; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Singaraju A; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Krishnan RK; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Kozoriz D; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA., Ma S; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Sankar V; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Notarbartolo S; Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Bellinzona, Switzerland.; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Infectious Diseases Unit, Milan, Italy., Buenrostro JD; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA.; Gene Regulation Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Sallusto F; Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Bellinzona, Switzerland.; Institute of Microbiology, ETH Zurich, Zurich, Switzerland., Patsopoulos NA; Systems Biology and Computer Science Program, Ann Romney Center for Neurological Diseases, Department of Neurology, Brigham & Women's Hospital, Boston, MA, USA.; Division of Genetics, Department of Medicine, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA.; Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Rozenblatt-Rosen O; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Genentech, South San Francisco, CA, USA., Kuchroo VK; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. vkuchroo@bwh.harvard.edu.; The Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. vkuchroo@bwh.harvard.edu., Regev A; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA. aviv.regev.sc@gmail.com.; Genentech, South San Francisco, CA, USA. aviv.regev.sc@gmail.com.
Jazyk: angličtina
Zdroj: Nature immunology [Nat Immunol] 2024 Aug; Vol. 25 (8), pp. 1395-1410. Date of Electronic Publication: 2024 Jul 15.
DOI: 10.1038/s41590-024-01901-1
Abstrakt: Interleukin-17 (IL-17)-producing helper T (T H 17) cells are heterogenous and consist of nonpathogenic T H 17 (npT H 17) cells that contribute to tissue homeostasis and pathogenic T H 17 (pT H 17) cells that mediate tissue inflammation. Here, we characterize regulatory pathways underlying T H 17 heterogeneity and discover substantial differences in the chromatin landscape of npT H 17 and pT H 17 cells both in vitro and in vivo. Compared to other CD4 + T cell subsets, npT H 17 cells share accessible chromatin configurations with regulatory T cells, whereas pT H 17 cells exhibit features of both npT H 17 cells and type 1 helper T (T H 1) cells. Integrating single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) and single-cell RNA sequencing (scRNA-seq), we infer self-reinforcing and mutually exclusive regulatory networks controlling different cell states and predicted transcription factors regulating T H 17 cell pathogenicity. We validate that BACH2 promotes immunomodulatory npT H 17 programs and restrains proinflammatory T H 1-like programs in T H 17 cells in vitro and in vivo. Furthermore, human genetics implicate BACH2 in multiple sclerosis. Overall, our work identifies regulators of T H 17 heterogeneity as potential targets to mitigate autoimmunity.
(© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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