Abstract
Peripherally derived regulatory T (pT(reg)) cell generation requires T-cell receptor (TCR) signalling and the cytokines TGF-β1 and IL-2. Here we show that TCR signalling induces the microRNA miR-31, which negatively regulates pT(reg)-cell generation. miR-31 conditional deletion results in enhanced induction of pT(reg) cells, and decreased severity of experimental autoimmune encephalomyelitis (EAE). Unexpectedly, we identify Gprc5a as a direct target of miR-31. Gprc5a is known as retinoic acid-inducible protein 3, and its deficiency leads to impaired pT(reg-)cell induction and increased EAE severity. By generating miR-31 and Gprc5a double knockout mice, we show that miR-31 promotes the development of EAE through inhibiting Gprc5a. Thus, our data identify miR-31 and its target Gprc5a as critical regulators for pT(reg)-cell generation, suggesting a previously unrecognized epigenetic mechanism for dysfunctional T(reg) cells in autoimmune diseases.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Blotting, Western
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Chromatin Immunoprecipitation
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Cytokines / immunology*
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Cytokines / metabolism
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Encephalomyelitis, Autoimmune, Experimental / genetics*
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Encephalomyelitis, Autoimmune, Experimental / immunology
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Encephalomyelitis, Autoimmune, Experimental / pathology
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Flow Cytometry
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Freund's Adjuvant
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Mice
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Mice, Knockout
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MicroRNAs / genetics*
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MicroRNAs / immunology
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Real-Time Polymerase Chain Reaction
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Receptors, Antigen, T-Cell / metabolism*
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Receptors, G-Protein-Coupled / immunology
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Receptors, G-Protein-Coupled / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Spinal Cord / immunology
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Spinal Cord / pathology
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T-Lymphocytes, Regulatory / cytology*
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T-Lymphocytes, Regulatory / immunology
Substances
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Cytokines
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GPRC5A protein, mouse
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MicroRNAs
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Mirn31 microRNA, mouse
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Receptors, Antigen, T-Cell
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Receptors, G-Protein-Coupled
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Freund's Adjuvant