MicroRNA-15/16 Antagonizes c-Myb to Control Natural Killer Cell Maturation

NK cells develop in the bone marrow and complete their maturation in peripheral organs, but the molecular events controlling maturation are incompletely understood. Utilizing an NK cell-specific miR-15/16 deficient genetic model (15aKO), we identified a critical role for miR-15/16 family microRNAs in the normal maturation of NK cells in vivo, with a specific reduction in mature CD11b+CD27- NK cells in multiple tissues. The mechanism responsible was a block in differentiation, since accelerated NK cell death was not evident, and earlier intermediates of NK cell maturation were expanded. Further, we identified Myb as a direct target of miR-15/16 in NK cells, with Myb expression increased in immature 15aKO NK cells. Following adoptive transfer, immature 15aKO NK cells exhibited defective maturation, which was rescued by ectopic miR-15/16 expression or Myb knockdown. Moreover, Myb overexpression resulted in defective NK cell maturation. Thus, miR-15/16 regulation of Myb controls the normal NK cell maturation program. 3 technical replicates each of CD27+ 15a/16-1FKO NK cells, and CD27+ Ctrl NK cells

NK细胞（NK cells）在骨髓中发育，并在外周器官中完成成熟，但调控其成熟的分子事件尚未完全阐明。本研究利用NK细胞特异性miR-15/16缺陷遗传模型（15aKO），鉴定出miR-15/16家族微RNA（microRNAs）在体内NK细胞正常成熟过程中的关键作用：该缺陷模型会导致多个组织内成熟CD11b+CD27- NK细胞出现特异性减少。其核心机制为分化阻滞——未观察到NK细胞死亡加速，且NK细胞成熟的早期中间态细胞发生扩增。本研究进一步发现，Myb是miR-15/16在NK细胞中的直接靶标，未成熟15aKO NK细胞中Myb的表达水平显著升高。过继转移实验显示，未成熟15aKO NK细胞的成熟功能存在缺陷，该缺陷可通过异位表达miR-15/16或敲低Myb得以挽救。此外，过表达Myb同样会引发NK细胞成熟缺陷。综上，miR-15/16通过调控Myb的表达，控制NK细胞的正常成熟程序。本研究对CD27+ 15a/16-1FKO NK细胞与CD27+ 对照NK细胞各设置了3次技术重复。