生物
白细胞介素21
淋巴因子激活杀伤细胞
脱颗粒
造血
白细胞介素12
细胞培养
细胞生物学
干细胞
分子生物学
癌症研究
T细胞
免疫学
体外
细胞毒性T细胞
受体
免疫系统
生物化学
遗传学
作者
Minghang Yu,Ziyang Su,Xuefeng Huang,Yujie Zhou,Xulong Zhang,Bingbing Wang,Zihan Wang,Yi Liu,Nianzeng Xing,Miaoran Xia,Xi Wang
标识
DOI:10.1002/jlb.1ma0321-155rr
摘要
NK cells are innate lymphoid cells that play important roles in tumor eradication and viral clearance. We previously found that deletion or inhibition of the histone methyltransferase Ezh2 (enhancer of zeste homolog 2) in hematopoietic stem and progenitor cells (HSPCs) from both mice and humans enhanced the commitment and cytotoxicity of NK cells to tumor cells. This study tested the hypothesis that inhibiting Ezh2, especially in NK lineage cells, could also affect NK cell development and function. We crossed Ezh2fl/fl mice with Ncr1iCre mice to delete the Ezh2 gene in immature NK cells and downstream progeny. Ezh2 deficiency increased the total number of NK cells and promoted NK cell terminal differentiation, as the percentages of the most mature CD27- CD11b+ subsets were increased. The NK cell cytotoxicity against tumor cells in vitro was enhanced, with increased degranulation and IFN-γ production. In addition, during the process of human NK cells differentiating from HSPCs , inhibiting EZH2 catalytic activity at day 14 (when NK lineage commitment began) also resulted in increased proportions of mature NK cells and cytotoxicity. Furthermore, RNA-seq and CUT&RUN-qPCR assays showed that the effects of Ezh2 may be based on its direct modulation of the expression of the transcription factor Pbx1 (pre-B-cell leukemia transcription factor 1), which has been reported to promote NK cell development. In summary, we demonstrate that Ezh2 is a negative regulator of NK cell terminal maturation and function.
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