1. Roquin Suppresses the PI3K-mTOR Signaling Pathway to Inhibit T Helper Cell Differentiation and Conversion of Treg to Tfr Cells
- Author
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Andreas Maiser, Joao C. Guimaraes, Heinrich Leonhardt, Martin Hrabĕ de Angelis, Desheng Hu, Dirk Baumjohann, Anne Krug, Timsse Raj, Mihaela Zavolan, Stefan Floess, Alexander F. Heiseke, Jochen Huehn, Thomas Brocker, Juliane Klein, Susan Marschall, Katharina Essig, Vigo Heissmeyer, Elfriede Noessner, Dominik Alterauge, Cornelis F. Calkhoven, Stephanie L. Edelmann, Gesine Behrens, and Jan Kranich
- Subjects
0301 basic medicine ,Cellular differentiation ,AUTOIMMUNITY ,Lymphocyte Activation ,T-Lymphocytes, Regulatory ,Mice ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,Immunology and Allergy ,IL-2 receptor ,B-Lymphocytes ,biology ,Forkhead Box Protein O1 ,TOR Serine-Threonine Kinases ,MTOR ,COSTIMULATOR MESSENGER-RNA ,GERMINAL CENTER REACTION ,Cell Differentiation ,Colitis ,Ubiquitin ligase ,Cell biology ,Infectious Diseases ,medicine.anatomical_structure ,Female ,Signal transduction ,Signal Transduction ,EXPRESSION ,Ubiquitin-Protein Ligases ,T cell ,Primary Cell Culture ,Immunology ,Mice, Transgenic ,TH17 DIFFERENTIATION ,03 medical and health sciences ,INFLAMMATION ,medicine ,Animals ,PI3K/AKT/mTOR pathway ,RECEPTOR ,Interleukin-2 Receptor alpha Subunit ,PTEN Phosphohydrolase ,Germinal center ,ROR-GAMMA ,Germinal Center ,Mice, Inbred C57BL ,Repressor Proteins ,Disease Models, Animal ,MicroRNAs ,030104 developmental biology ,Gene Expression Regulation ,T cell differentiation ,biology.protein ,Th17 Cells ,Spleen ,EFFECTOR LINEAGE ,030215 immunology - 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.
- Published
- 2017