Transcription factor TCF1 binds to RORγt and orchestrates a regulatory network that determines homeostatic Th17 cell state.

Autor:	Mangani D; Gene Lay Institute of Immunology and Inflammation, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera Italiana, Bellinzona 6500, Switzerland., Subramanian A; Gene Lay Institute of Immunology and Inflammation, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Huang L; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA., Cheng H; Gene Lay Institute of Immunology and Inflammation, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA., Krovi SH; Gene Lay Institute of Immunology and Inflammation, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA., Wu Y; Gene Lay Institute of Immunology and Inflammation, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Yang D; Gene Lay Institute of Immunology and Inflammation, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA., Moreira TG; Gene Lay Institute of Immunology and Inflammation, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA., Escobar G; Gene Lay Institute of Immunology and Inflammation, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA., Schnell A; Gene Lay Institute of Immunology and Inflammation, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Dixon KO; Gene Lay Institute of Immunology and Inflammation, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA., Krishnan RK; Gene Lay Institute of Immunology and Inflammation, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA., Singh V; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Sobel RA; Department of Pathology, Stanford University, Stanford, CA 94304, USA., Weiner HL; Gene Lay Institute of Immunology and Inflammation, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA., Kuchroo VK; Gene Lay Institute of Immunology and Inflammation, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Anderson AC; Gene Lay Institute of Immunology and Inflammation, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: acanderson@bwh.harvard.edu.
Jazyk:	angličtina
Zdroj:	Immunity [Immunity] 2024 Oct 15. Date of Electronic Publication: 2024 Oct 15.
DOI:	10.1016/j.immuni.2024.09.017
Abstrakt:	T helper (Th) 17 cells encompass a spectrum of cell states, including cells that maintain homeostatic tissue functions and pro-inflammatory cells that can drive autoimmune tissue damage. Identifying regulators that determine Th17 cell states can identify ways to control tissue inflammation and restore homeostasis. Here, we found that interleukin (IL)-23, a cytokine critical for inducing pro-inflammatory Th17 cells, decreased transcription factor T cell factor 1 (TCF1) expression. Conditional deletion of TCF1 in mature T cells increased the pro-inflammatory potential of Th17 cells, even in the absence of IL-23 receptor signaling, and conferred pro-inflammatory potential to homeostatic Th17 cells. Conversely, sustained TCF1 expression decreased pro-inflammatory Th17 potential. Mechanistically, TCF1 bound to RORγt, thereby interfering with its pro-inflammatory functions, and orchestrated a regulatory network that determined Th17 cell state. Our findings identify TCF1 as a major determinant of Th17 cell state and provide important insight for the development of therapies for Th17-driven inflammatory diseases. Competing Interests: Declaration of interests A.C.A. is a member of the SAB for Tizona Therapeutics, Trishula Therapeutics, Compass Therapeutics, and Zumutor Biologics. A.C.A. is also a paid consultant for Excepgen. V.K.K. is a co-founder, has an ownership interest in, and is a member of SAB of Celsius Therapeutics, Tizona Therapeutics, Larkspur Biosciences, and Trishula Therapeutics. V.K.K. is also the chair of the board and has equity interests in Bicara Therapeutics. H.L.W. is a member of the SAB for Tiziana Life Sciences and vTv Therapeutics and has stock in vTv Therapeutics. A.C.A.’s, V.K.K.’s, and H.L.W.’s interests were reviewed and managed by the Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflict-of-interest policies. The authors have filed a patent related to this work. (Copyright © 2024 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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