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

Immunity. 2017 Dec 19;47(6):1067-1082.e12. doi: 10.1016/j.immuni.2017.11.008. Epub 2017 Dec 12.

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.

Keywords: Akt mTOR; CD25; Foxo1; Itch; Pten; RNA-binding proteins; Roquin; T cell differentiation; Tfh; Tfr.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / pathology
  • Cell Differentiation
  • Colitis / genetics
  • Colitis / immunology*
  • Colitis / pathology
  • Disease Models, Animal
  • Female
  • Forkhead Box Protein O1 / genetics
  • Forkhead Box Protein O1 / immunology
  • Gene Expression Regulation
  • Germinal Center / immunology
  • Germinal Center / pathology
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics
  • MicroRNAs / immunology
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / immunology
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / immunology*
  • Primary Cell Culture
  • Repressor Proteins / deficiency
  • Repressor Proteins / genetics
  • Repressor Proteins / immunology*
  • Signal Transduction
  • Spleen / immunology
  • Spleen / pathology
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / pathology
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / immunology*
  • Th17 Cells / immunology
  • Th17 Cells / pathology
  • Ubiquitin-Protein Ligases / deficiency
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / immunology*

Substances

  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Il2ra protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • MIRN17-92 microRNA, mouse
  • MicroRNAs
  • Repressor Proteins
  • roquin-2 protein, mouse
  • Itch protein, mouse
  • Rc3h1 protein, mouse
  • Ubiquitin-Protein Ligases
  • Phosphatidylinositol 3-Kinases
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • PTEN Phosphohydrolase
  • Pten protein, mouse