title: microRNA-mediated regulation of mTOR complex components facilitates discrimination between activation and anergy in CD4 T cells.
abstract: 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.
authors.affiliation: Lymphocyte Development Group and Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, England, UK Lymphocyte Development Group and Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, England, UK CIRI, International Center for Infectiology Research, Université de Lyon, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Ecole Normale Supérieure, 69007 Lyon, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Marcais
authors.affiliation: Lymphocyte Development Group and Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, England, UK Lymphocyte Development Group and Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, England, UK.
authors.forename: Rory
authors.initials: R
authors.lastname: Blevins
authors.affiliation: Department of Proteomics and Signal Transduction, Max-Planck Institute for Biochemistry, 82152 Martinsried, Germany Weill Cornell Medical College in Qatar, Qatar Foundation, Education City, Doha, State of Qatar.
authors.forename: Johannes
authors.initials: J
authors.lastname: Graumann
authors.affiliation: Lymphocyte Development Group and Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, England, UK Lymphocyte Development Group and Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, England, UK.
authors.forename: Amelie
authors.initials: A
authors.lastname: Feytout
authors.affiliation: Lymphocyte Development Group and Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, England, UK.
authors.forename: Gopuraja
authors.initials: G
authors.lastname: Dharmalingam
authors.affiliation: Lymphocyte Development Group and Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, England, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Carroll
authors.affiliation: Unité de Biologie des Populations Lymphocytaires, Department of Immunology, Institut Pasteur, and Centre National pour la Recherche Scientifique (Centre National de la Recherche Scientifique), URA1961, 75724 Paris, France Graduate Program in Areas of Basic and Applied Biology (GABBA), Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal.
authors.forename: Inês F
authors.initials: IF
authors.lastname: Amado
authors.affiliation: Lymphocyte Development Group and Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, England, UK Lymphocyte Development Group and Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, England, UK.
authors.forename: Ludovica
authors.initials: L
authors.lastname: Bruno
authors.affiliation: Department of Pathology, Microbiology, and Immunology and Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Keunwook
authors.initials: K
authors.lastname: Lee
authors.affiliation: CIRI, International Center for Infectiology Research, Université de Lyon, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Ecole Normale Supérieure, 69007 Lyon, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Walzer
authors.affiliation: Department of Proteomics and Signal Transduction, Max-Planck Institute for Biochemistry, 82152 Martinsried, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Mann
authors.affiliation: Unité de Biologie des Populations Lymphocytaires, Department of Immunology, Institut Pasteur, and Centre National pour la Recherche Scientifique (Centre National de la Recherche Scientifique), URA1961, 75724 Paris, France.
authors.forename: Antonio A
authors.initials: AA
authors.lastname: Freitas
authors.affiliation: Department of Pathology, Microbiology, and Immunology and Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232 Department of Pathology, Microbiology, and Immunology and Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Mark
authors.initials: M
authors.lastname: Boothby
authors.affiliation: Lymphocyte Development Group and Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, England, UK Lymphocyte Development Group and Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, England, UK.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Fisher
authors.affiliation: Lymphocyte Development Group and Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, England, UK Lymphocyte Development Group and Epigenetics Section, MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College London, London W12 0NN, England, UK matthias.merkenschlager@csc.mrc.ac.uk.
authors.forename: Matthias
authors.initials: M
authors.lastname: Merkenschlager
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D017635:Clonal Anergy / Q000235:genetics* / Q000276:immunology*; D005786:Gene Expression Regulation; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D043244:Ribonuclease III / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D007376:Interleukin-2; D035683:MicroRNAs; D011948:Receptors, Antigen, T-Cell; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D043244:Ribonuclease III