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 Hrabĕ 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 journalArticlepeer-review

107 Scopus citations

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∼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. Essig et al. show that spontaneous activation and aberrant differentiation of Roquin-deficient T cells involves cell-intrinsic causes in not only conventional T cells but also impaired Treg cell function. In both cell types, Roquin inhibits the PI3K-mTOR signaling pathway at several levels, thereby controlling protein biosynthesis and limiting differentiation toward Th17 and Tfh cells as well as preventing the conversion and functional specialization of Treg into Tfr cells.

Original languageEnglish
Pages (from-to)1067-1082.e12
JournalImmunity
Volume47
Issue number6
DOIs
StatePublished - 19 Dec 2017
Externally publishedYes

Keywords

  • Akt mTOR
  • CD25
  • Foxo1
  • Itch
  • Pten
  • RNA-binding proteins
  • Roquin
  • T cell differentiation
  • Tfh
  • Tfr

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