NFAT primes the human RORC locus for RORγt expression in CD4+ T cells

Hanane Yahia-Cherbal, Magda Rybczynska, Domenica Lovecchio, Tharshana Stephen, Chloé Lescale, Katarzyna Placek, Jérome Larghero, Lars Rogge and Elisabetta Bianchi ()
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Hanane Yahia-Cherbal: Institut Pasteur, Immunoregulation Unit, Department of Immunology
Magda Rybczynska: Institut Pasteur, Immunoregulation Unit, Department of Immunology
Domenica Lovecchio: Institut Pasteur, Immunoregulation Unit, Department of Immunology
Tharshana Stephen: Institut Pasteur, Unité de Technologie et Service Cytométrie et Biomarqueurs (UTechS CB), Centre de recherche translationnelle (CRT)
Chloé Lescale: Institut Pasteur, Genome Integrity, Immunity and Cancer Unit, Equipe Labellisée Ligue Contre le Cancer, Department of Immunology, Department of Genomes and Genetics
Katarzyna Placek: Institut Pasteur, Immunoregulation Unit, Department of Immunology
Jérome Larghero: Assistance Publique-Hopitaux de Paris, Hôpital Saint-Louis, Cell Therapy Unit and Cord Blood Bank; CIC de Biothérapies
Lars Rogge: Institut Pasteur, Immunoregulation Unit, Department of Immunology
Elisabetta Bianchi: Institut Pasteur, Immunoregulation Unit, Department of Immunology

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: Abstract T helper 17 (Th17) cells have crucial functions in mucosal immunity and the pathogenesis of several chronic inflammatory diseases. The lineage-specific transcription factor, RORγt, encoded by the RORC gene modulates Th17 polarization and function, as well as thymocyte development. Here we define several regulatory elements at the human RORC locus in thymocytes and peripheral CD4+ T lymphocytes, with CRISPR/Cas9-guided deletion of these genomic segments supporting their role in RORγt expression. Mechanistically, T cell receptor stimulation induces cyclosporine A-sensitive histone modifications and P300/CBP acetylase recruitment at these elements in activated CD4+ T cells. Meanwhile, NFAT proteins bind to these regulatory elements and activate RORγt transcription in cooperation with NF-kB. Our data thus demonstrate that NFAT specifically regulate RORγt expression by binding to the RORC locus and promoting its permissive conformation.

Date: 2019
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DOI: 10.1038/s41467-019-12680-x

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