National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433, China.
J Immunol. 2012 Jul 1;189(1):211-21. doi: 10.4049/jimmunol.1200609. Epub 2012 May 30.
NK cells are important innate immune cells with potent cytotoxicity that can be activated by type I IFN from the host once infected. How NK cell cytotoxicity is activated by type I IFN and then tightly regulated remain to be fully elucidated. MicroRNAs (miRNAs, or miRs) are important regulators of innate immune response, but the full scale of miRNome in human NK cells remains to be determined. In this study, we reported an in-depth analysis of miRNomes in resting and IFN-α-activated human NK cells, found two abundant miRNAs, miR-378 and miR-30e, markedly decreased in activated NK cells by IFN-α, and further proved that miR-378 and miR-30e directly targeted granzyme B and perforin, respectively. Thus, IFN-α activation suppresses miR-378 and miR-30e expression to release cytolytic molecule mRNAs for their protein translation and then augments NK cell cytotoxicity. Importantly, the phenomena are also confirmed in human NK cells activated by other cytokines and even in the sorted CD16(+)CD56(dim)CD69(+) human NK cell subset. Finally, miR-378 and miR-30e were proved to be suppressors of human NK cell cytotoxicity. Taken together, our results reveal that downregulated miR-378 and miR-30e during NK cell activation are negative regulators of human NK cell cytotoxicity, providing a mechanistic explanation for regulation of NK cell function by miRNAs.
自然杀伤 (NK) 细胞是具有强大细胞毒性的重要先天免疫细胞，一旦被感染，宿主的 I 型干扰素 (IFN) 就能激活它们。NK 细胞的细胞毒性如何被 I 型 IFN 激活，然后又如何被紧密调控，这些仍有待充分阐明。微小 RNA（miRNA，或 miRs）是先天免疫反应的重要调控因子，但人类 NK 细胞的 miRNome 的全貌仍有待确定。在这项研究中，我们报道了对静息和 IFN-α 激活的人 NK 细胞中的 miRNome 的深入分析，发现了两种丰富的 miRNA，miR-378 和 miR-30e，在 IFN-α 激活的 NK 细胞中显著减少，并进一步证明 miR-378 和 miR-30e 分别直接靶向颗粒酶 B 和穿孔素。因此，IFN-α 激活抑制 miR-378 和 miR-30e 的表达，释放细胞毒性分子的 mRNA 进行其蛋白翻译，从而增强 NK 细胞的细胞毒性。重要的是，这些现象在其他细胞因子激活的人类 NK 细胞中甚至在分选的 CD16(+)CD56(dim)CD69(+)人类 NK 细胞亚群中也得到了证实。最后，miR-378 和 miR-30e 被证明是人类 NK 细胞细胞毒性的抑制剂。总之，我们的结果表明，在 NK 细胞激活过程中 miR-378 和 miR-30e 的下调是人类 NK 细胞细胞毒性的负调控因子，为 miRNA 对 NK 细胞功能的调控提供了机制解释。
