Yun Sohyun, Lee Su Ui, Kim Jung Min, Lee Hyun-Jun, Song Hae Young, Kim Young Kyeung, Jung Haiyoung, Park Young-Jun, Yoon Suk Ran, Oh Sei-Ryang, Kim Tae-Don, Choi Inpyo
Immunotherapy Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Republic of Korea.
Natural Medicine Research Center, Korea Research Institute of Bioscience and Biotechnology, Ochang-eup, Republic of Korea.
PLoS One. 2014 Oct 14;9(10):e108913. doi: 10.1371/journal.pone.0108913. eCollection 2014.
Natural killer (NK) cells are innate immune effector cells that protect against cancer and some viral infections. Until recently, most studies have investigated the molecular signatures of human or mouse NK cells to identify genes that are specifically expressed during NK cell development. However, the mechanism regulating NK cell development remains unclear. Here, we report a regulatory network of potential interactions during in vitro differentiation of human NK cells, identified using genome-wide mRNA and miRNA databases through hierarchical clustering analysis, gene ontology analysis and a miRNA target prediction program. The microRNA (miR)-583, which demonstrated the largest ratio change in mature NK cells, was highly correlated with IL2 receptor gamma (IL2Rγ) expression. The overexpression of miR-583 had an inhibitory effect on NK cell differentiation. In a reporter assay, the suppressive effect of miR-583 was ablated by mutating the putative miR-583 binding site of the IL2Rγ 3' UTR. Therefore, we show that miR-583 acts as a negative regulator of NK cell differentiation by silencing IL2Rγ. Additionally, we provide a comprehensive database of genome-wide mRNA and miRNA expression during human NK cell differentiation, offering a better understanding of basic human NK cell biology for the application of human NK cells in immunotherapy.
自然杀伤（NK）细胞是先天性免疫效应细胞，可抵御癌症和某些病毒感染。直到最近，大多数研究都在调查人类或小鼠NK细胞的分子特征，以鉴定在NK细胞发育过程中特异性表达的基因。然而，调节NK细胞发育的机制仍不清楚。在此，我们报告了人类NK细胞体外分化过程中潜在相互作用的调控网络，该网络是通过层次聚类分析、基因本体分析和miRNA靶标预测程序，利用全基因组mRNA和miRNA数据库鉴定出来的。在成熟NK细胞中显示出最大比例变化的微小RNA（miR）-583与白细胞介素2受体γ（IL2Rγ）的表达高度相关。miR-583的过表达对NK细胞分化具有抑制作用。在报告基因检测中，通过突变IL2Rγ 3'UTR的假定miR-583结合位点，消除了miR-583的抑制作用。因此，我们表明miR-583通过使IL2Rγ沉默而作为NK细胞分化的负调节因子。此外，我们提供了人类NK细胞分化过程中全基因组mRNA和miRNA表达的综合数据库，有助于更好地理解人类NK细胞的基础生物学，以便将人类NK细胞应用于免疫治疗。
