Torri Anna, Carpi Donatella, Bulgheroni Elisabetta, Crosti Maria-Cristina, Moro Monica, Gruarin Paola, Rossi Riccardo L, Rossetti Grazisa, Di Vizio Dolores, Hoxha Mirjam, Bollati Valentina, Gagliani Cristina, Tacchetti Carlo, Paroni Moira, Geginat Jens, Corti Laura, Venegoni Luigia, Berti Emilio, Pagani Massimiliano, Matarese Giuseppe, Abrignani Sergio, de Candia Paola
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.
J Biol Chem. 2017 Feb 17;292(7):2903-2915. doi: 10.1074/jbc.M116.769893. Epub 2017 Jan 11.
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 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 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 and their biological effect in cell to cell communication during the adaptive immune response.
在T细胞受体受到刺激后，CD4辅助性T（Th）淋巴细胞会释放含有微小RNA的细胞外囊泡（EVs）。然而，关于人类CD4 T细胞亚群是否会释放含有不同微小RNA模式的EVs，目前尚无相关数据。本研究旨在通过评估Th1、Th17和调节性T（Treg）细胞在T细胞受体刺激后释放的EVs中的微小RNA含量来填补这一空白。我们的结果表明，Treg细胞释放的EVs与其他亚群释放的EVs有显著差异。特别是，miR-146a-5p、miR-150-5p和miR-21-5p在Treg来源的EVs中富集，而miR-106a-5p、miR-155-5p和miR-19a-3p则在Treg来源的EVs中减少。在银屑病自身免疫患者的血清中，所鉴定的与EV相关的微小RNA特征增加，而在用依那西普进行有效治疗后恢复到健康水平，依那西普是一种靶向TNF途径并抑制炎症的生物药物。此外，基因集富集分析显示，在Treg来源的EV微小RNA的验证靶标列表中，与T细胞活化相关的基因如CD40L、IRAK1、IRAK2、STAT1和c-Myb有过度表达。在功能水平上，Treg来源的（而非Th1/Th17来源的）EVs抑制CD4 T细胞增殖，并抑制miR-146a-5p的两个相关靶标：STAT1和IRAK2。总之，我们的研究确定了不同人类CD4 T细胞亚群特异性释放的微小RNA，并开始揭示它们在人类血清中的数量在标记这些细胞的病理激发及其在适应性免疫反应中细胞间通讯的生物学效应方面的潜在用途。
