1. microRNA-mediated regulation of mTOR complex components facilitates discrimination between activation and anergy in CD4 T cells
- Author
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Antoine Marçais, Keunwook Lee, Amanda G. Fisher, Johannes Graumann, Antonio A. Freitas, Thomas L. Carroll, Rory Blevins, Ludovica Bruno, Inês F. Amado, Matthias Mann, Amelie Feytout, Mark Boothby, Matthias Merkenschlager, Gopuraja Dharmalingam, Thierry Walzer, Réponse immunitaire innée dans les maladies infectieuses et auto-immunes – Innate immunity in infectious and autoimmune diseases, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Lymphocyte development group, MRC, London, Imperial College London, Epigenetics, Department of Proteomics and Signal Transduction, Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Biologie des Populations Lymphocytaires, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Graduate Program in Areas of Basic and Applied Biology (GABBA), Universidade do Porto = University of Porto, Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine [Nashville], This work was supported by the Medical Research Council UK and a post-doctoral fellowship from Fondation Pour la Recherche Médicale (AM)., Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Max Planck Institute of Biochemistry (MPIB), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], and Universidade do Porto
- Subjects
CD4-Positive T-Lymphocytes ,Ribonuclease III ,T cell ,Immunology ,Receptors, Antigen, T-Cell ,Mice, Transgenic ,Biology ,Lymphocyte Activation ,mTORC2 ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Lymphocyte costimulation ,medicine ,Animals ,Humans ,Immunology and Allergy ,Phosphorylation ,Protein kinase B ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,Clonal Anergy ,0303 health sciences ,Binding Sites ,Base Sequence ,Clonal anergy ,TOR Serine-Threonine Kinases ,RPTOR ,T-cell receptor ,Cell Biology ,Molecular biology ,Cell biology ,enzymes and coenzymes (carbohydrates) ,MicroRNAs ,medicine.anatomical_structure ,Gene Expression Regulation ,Interleukin-2 ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Proto-Oncogene Proteins c-akt ,030215 immunology ,Signal Transduction - Abstract
Using Dicer-deficient CD4 T cells, Marcais et al. show that microRNAs regulate the expression of mTOR components that are needed to discriminate between activating and anergy-inducing stimuli., T cell receptor (TCR) signals can elicit full activation with acquisition of effector functions or a state of anergy. Here, we ask whether microRNAs affect the interpretation of TCR signaling. We find that Dicer-deficient CD4 T cells fail to correctly discriminate between activating and anergy-inducing stimuli and produce IL-2 in the absence of co-stimulation. Excess IL-2 production by Dicer-deficient CD4 T cells was sufficient to override anergy induction in WT T cells and to restore inducible Foxp3 expression in Il2-deficient CD4 T cells. Phosphorylation of Akt on S473 and of S6 ribosomal protein was increased and sustained in Dicer-deficient CD4 T cells, indicating elevated mTOR activity. The mTOR components Mtor and Rictor were posttranscriptionally deregulated, and the microRNAs Let-7 and miR-16 targeted the Mtor and Rictor mRNAs. Remarkably, returning Mtor and Rictor to normal levels by deleting one allele of Mtor and one allele of Rictor was sufficient to reduce Akt S473 phosphorylation and to reduce co-stimulation–independent IL-2 production in Dicer-deficient CD4 T cells. These results show that microRNAs regulate the expression of mTOR components in T cells, and that this regulation is critical for the modulation of mTOR activity. Hence, microRNAs contribute to the discrimination between T cell activation and anergy.
- Published
- 2014
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