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

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  • Hanane Yahia-Cherbal

    (Institut Pasteur, Immunoregulation Unit, Department of Immunology
    Université Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur)

  • Magda Rybczynska

    (Institut Pasteur, Immunoregulation Unit, Department of Immunology
    École supérieure de Physique et de Chimie industrielles)

  • 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
    University of Bonn)

  • 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)

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.

Suggested Citation

  • Hanane Yahia-Cherbal & Magda Rybczynska & Domenica Lovecchio & Tharshana Stephen & Chloé Lescale & Katarzyna Placek & Jérome Larghero & Lars Rogge & Elisabetta Bianchi, 2019. "NFAT primes the human RORC locus for RORγt expression in CD4+ T cells," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12680-x
    DOI: 10.1038/s41467-019-12680-x
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