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

Davide Mangani¹, Ayshwarya Subramanian², Linglin Huang³, Hanning Cheng⁴, S Harsha Krovi⁴, Yufan Wu², Dandan Yang⁴, Thais G Moreira⁴, Giulia Escobar⁴, Alexandra Schnell², Karen O Dixon⁴, Rajesh K Krishnan⁴, Vasundhara Singh⁵, Raymond A Sobel⁶, Howard L Weiner⁴, Vijay K Kuchroo², Ana C Anderson⁷

Affiliations

¹ 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.
² 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.
³ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
⁴ Gene Lay Institute of Immunology and Inflammation, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁶ Department of Pathology, Stanford University, Stanford, CA 94304, USA.
⁷ 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.

PMID: 39447575
PMCID: PMC11614491 (available on 2025-11-12)
DOI: 10.1016/j.immuni.2024.09.017

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

Davide Mangani et al. Immunity. 2024.

. 2024 Nov 12;57(11):2565-2582.e6.

doi: 10.1016/j.immuni.2024.09.017. Epub 2024 Oct 23.

Authors

Affiliations

¹ 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.
² 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.
³ Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
⁴ Gene Lay Institute of Immunology and Inflammation, Ann Romney Center for Neurologic Diseases, Harvard Medical School and Mass General Brigham, Boston, MA 02115, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁶ Department of Pathology, Stanford University, Stanford, CA 94304, USA.
⁷ 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.

PMID: 39447575
PMCID: PMC11614491 (available on 2025-11-12)
DOI: 10.1016/j.immuni.2024.09.017

Abstract

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.

Keywords: IL-23; RORγt; TCF1; Th17; autoimmunity; multiple sclerosis.

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Conflict of interest statement

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.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Molecular Biology Databases