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 Krug; Mihaela Zavolan; Dirk Baumjohann; Vigo Heissmeyer

doi:10.1016/j.immuni.2017.11.008

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.

Authors

Katharina Essig¹, Desheng Hu², Joao C Guimaraes³, Dominik Alterauge¹, Stephanie Edelmann⁴, Timsse Raj¹, Jan Kranich¹, Gesine Behrens¹, Alexander Heiseke¹, Stefan Floess⁵, Juliane Klein¹, Andreas Maiser⁶, Susan Marschall⁷, Martin Hrabĕ de Angelis⁷, Heinrich Leonhardt⁶, Cornelis F Calkhoven⁸, Elfriede Noessner⁹, Thomas Brocker¹, Jochen Huehn⁵, Anne B Krug¹, Mihaela Zavolan³, Dirk Baumjohann¹, Vigo Heissmeyer¹⁰

Affiliations

¹ Institute for Immunology, Biomedical Center, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany.
² Institute for Immunology, Biomedical Center, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany. Electronic address: [email protected].
³ Computational and Systems Biology, Biozentrum, University of Basel, 4056 Basel, Switzerland.
⁴ Research Unit Molecular Immune Regulation, Helmholtz Zentrum München, 81377 München, Germany.
⁵ Experimental Immunology, Helmholtz Centre for Infection Research, 38124 Braunschweig, Germany.
⁶ Center for Integrated Protein Science, Department of Biology, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany.
⁷ German Center for Diabetes Research (DZD), 85764 Neuherberg, German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, 85764 Neuherberg, Chair of Experimental Genetics, School of Life Science Weihenstephan, Technische Universität München, Freising 85353, Germany.
⁸ European Research Institute for the Biology of Ageing (ERIBA), University Medical Center Groningen, University of Groningen, 9700 AD Groningen, the Netherlands.
⁹ Immunoanalytics Core Facility, Helmholtz Zentrum München, 81377 München, Germany.
¹⁰ Institute for Immunology, Biomedical Center, Ludwig-Maximilians-Universität München, 82152 Planegg-Martinsried, Germany; Research Unit Molecular Immune Regulation, Helmholtz Zentrum München, 81377 München, Germany. Electronic address: [email protected].

PMID: 29246441
DOI: 10.1016/j.immuni.2017.11.008

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.

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
mTOR protein, mouse
TOR Serine-Threonine Kinases
PTEN Phosphohydrolase
Pten protein, mouse