Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells

Katharina Essig, Desheng Hu, Joao C. Guimaraes, Dominik Alterauge, Stephanie Edelmann, Timsse Raj, Jan Kranich, Gesine Behrens, Alexander Heiseke, Stefan Floess, Juliane Klein, Andreas Maiser, Susan Marschall, Martin Hrabe de Angelis, Heinrich Leonhardt, Cornelis F. Calkhoven, Elfriede Noessner, Thomas Brocker, Jochen Huehn, Anne B. KrugMihaela Zavolan, Dirk Baumjohann, Vigo Heissmeyer

    Research output: Contribution to journalArticleAcademicpeer-review

    45 Citations (Scopus)

    Abstract

    Roquin proteins preclude spontaneous T cell activation and aberrant differentiation of T follicular helper (Tfh) or T helper 17 (Th17) cells. Here we showed that deletion of Roquin-encoding alleles specifically in regulatory T (Treg) cells also caused the activation of conventional T cells. Roquin-deficient Treg cells downregulated CD25, acquired a follicular Treg (Tfr) cell phenotype, and suppressed germinal center reactions but could not protect from colitis. Roquin inhibited the PI3K-mTOR signaling pathway by upregulation of Pten through interfering with miR-17 similar to 92 binding to an overlapping cis-element in the Pten 3' UTR, and downregulated the Foxo1-specific E3 ubiquitin ligase Itch. Loss of Roquin enhanced Akt-mTOR signaling and protein synthesis, whereas inhibition of PI3K or mTOR in Roquin-deficient T cells corrected enhanced Tfh and Th17 or reduced iTreg cell differentiation. Thereby, Roquin-mediated control of PI3K-mTOR signaling prevents autoimmunity by restraining activation and differentiation of conventional T cells and specialization of Treg cells.

    Original languageEnglish
    Pages (from-to)1067-1082.e12
    Number of pages28
    JournalImmunity
    Volume47
    Issue number6
    DOIs
    Publication statusPublished - 19-Dec-2017

    Keywords

    • COSTIMULATOR MESSENGER-RNA
    • GERMINAL CENTER REACTION
    • TH17 DIFFERENTIATION
    • EFFECTOR LINEAGE
    • ROR-GAMMA
    • EXPRESSION
    • MTOR
    • AUTOIMMUNITY
    • INFLAMMATION
    • RECEPTOR

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