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J Biol Chem. 2017 Feb 17;292(7):2903-2915. doi: 10.1074/jbc.M116.769893. Epub 2017 Jan 11.

Extracellular MicroRNA Signature of Human Helper T Cell Subsets in Health and Autoimmunity.

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From the INGM Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi," 20122 Milan, Italy.
the Division of Cancer Biology and Therapeutics, Departments of Surgery, Biomedical Sciences and Pathology and Laboratory Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California 90048.
the Laboratorio di Epidemiologia Molecolare e Epigenetica Ambientale, Dipartimento di Scienze Cliniche e di Comunità.
the Dipartimento di Medicina Sperimentale, Università di Genova, 16132 Genova, Italy.
the Dipartimento di Dermatologia, Fondazione IRCCS_Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy.
the Dipartimento di Fisiopatologia Medico-Chirurgica e dei Trapianti.
the Dipartimento di Medicina, Università degli Studi di Milano Bicocca, 20126 Milan, Italy.
the Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, and.
the Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, 80131 Naples, Italy, and
From the INGM Istituto Nazionale Genetica Molecolare "Romeo ed Enrica Invernizzi," 20122 Milan, Italy,
the DISCCO Dipartimento di Scienze Cliniche e di Comunità, Università di Milano, 20122 Milan, Italy.
the IRCCS Istituto di Ricovero e Cura a Carattere Scientifico MultiMedica, 20138 Milan, Italy


Upon T cell receptor stimulation, CD4+ T helper (Th) lymphocytes release extracellular vesicles (EVs) containing microRNAs. However, no data are available on whether human CD4+ T cell subsets release EVs containing different pattern of microRNAs. The present work aimed at filling this gap by assessing the microRNA content in EVs released upon in vitro T cell receptor stimulation of Th1, Th17, and T regulatory (Treg) cells. Our results indicate that EVs released by Treg cells are significantly different compared with those released by the other subsets. In particular, miR-146a-5p, miR-150-5p, and miR-21-5p are enriched, whereas miR-106a-5p, miR-155-5p, and miR-19a-3p are depleted in Treg-derived EVs. The in vitro identified EV-associated microRNA signature was increased in serum of autoimmune patients with psoriasis and returned to healthy levels upon effective treatment with etanercept, a biological drug targeting the TNF pathway and suppressing inflammation. Moreover, Gene Set Enrichment Analysis showed an over-representation of genes relevant for T cell activation, such as CD40L, IRAK1, IRAK2, STAT1, and c-Myb in the list of validated targets of Treg-derived EV miRNAs. At functional level, Treg-derived (but not Th1/Th17-derived) EVs inhibited CD4+ T cell proliferation and suppressed two relevant targets of miR-146a-5p: STAT1 and IRAK2. In conclusion, our work identified the miRNAs specifically released by different human CD4+ T cell subsets and started to unveil the potential use of their quantity in human serum to mark the pathological elicitation of these cells in vivo and their biological effect in cell to cell communication during the adaptive immune response.


autoimmunity; cell-cell interaction; extracellular vesicles; lymphocyte; microRNA (miRNA)

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