Department of Immunology, Research Center on Pediatric Development and Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, State Key Laboratory of Medical Molecular Biology, 100005, Beijing, China.
Institute of blood transfusion, Qingdao Blood Center, 266071, Qingdao, China.
Cell Mol Immunol. 2019 Feb;16(2):112-125. doi: 10.1038/cmi.2017.164. Epub 2018 Feb 12.
As an important component of innate immunity, human circulating γδ T cells function in rapid responses to infections and tumorigenesis. MicroRNAs (miRNAs) play a critical regulatory role in multiple biological processes and diseases. Therefore, how the functions of circulating human γδ T cells are regulated by miRNAs merits investigation. In this study, we profiled the miRNA expression patterns in human peripheral γδ T cells from 21 healthy donors and identified 14 miRNAs that were differentially expressed between peripheral αβ T cells and γδ T cells. Of the 14 identified genes, 7 miRNAs were downregulated, including miR-150-5p, miR-450a-5p, miR-193b-3p, miR-365a-3p, miR-31-5p, miR-125b-5p and miR-99a-5p, whereas the other 7 miRNAs were upregulated, including miR-34a-5p, miR-16-5p, miR-15b-5p, miR-24-3p, miR-22-3p, miR-22-5p and miR-9-5p, in γδ T cells compared with αβ T cells. In subsequent functional studies, we found that both miR-125b-5p and miR-99a-5p downregulated γδ T cell activation and cytotoxicity to tumor cells. Overexpression of miR-125b-5p or miR-99a-5p in γδ T cells inhibited γδ T cell activation and promoted γδ T cell apoptosis. Additionally, miR-125b-5p knockdown facilitated the cytotoxicity of γδ T cells toward tumor cells in vitro by increasing degranulation and secretion of IFN-γ and TNF-α. Our findings improve the understanding of the regulatory functions of miRNAs in γδ T cell activation and cytotoxicity, which has implications for interventional approaches to γδ T cell-mediated cancer therapy.
作为固有免疫的重要组成部分，人类循环 γδ T 细胞在快速应对感染和肿瘤发生方面发挥作用。microRNAs（miRNAs）在多种生物过程和疾病中发挥着关键的调节作用。因此，miRNAs 如何调节循环人类 γδ T 细胞的功能值得研究。在这项研究中，我们对 21 名健康供体的外周血 γδ T 细胞中的 miRNA 表达谱进行了分析，鉴定出 14 种在外周血 αβ T 细胞和 γδ T 细胞之间差异表达的 miRNA。在鉴定出的 14 个基因中，有 7 个 miRNA 下调，包括 miR-150-5p、miR-450a-5p、miR-193b-3p、miR-365a-3p、miR-31-5p、miR-125b-5p 和 miR-99a-5p，而另外 7 个 miRNA 上调，包括 miR-34a-5p、miR-16-5p、miR-15b-5p、miR-24-3p、miR-22-3p、miR-22-5p 和 miR-9-5p，在 γδ T 细胞中与 αβ T 细胞相比。在随后的功能研究中，我们发现 miR-125b-5p 和 miR-99a-5p 均可下调 γδ T 细胞的激活和对肿瘤细胞的细胞毒性。在 γδ T 细胞中过表达 miR-125b-5p 或 miR-99a-5p 可抑制 γδ T 细胞的激活并促进 γδ T 细胞凋亡。此外，miR-125b-5p 的敲低通过增加脱颗粒和 IFN-γ 和 TNF-α 的分泌，促进体外 γδ T 细胞对肿瘤细胞的细胞毒性。我们的研究结果提高了对 miRNA 在 γδ T 细胞激活和细胞毒性中的调节作用的认识，这对 γδ T 细胞介导的癌症治疗的干预方法具有重要意义。
