Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China.
Department of Immunology, School of Basic Medical Sciences; Advanced Innovation Center for Human Brain Protection, Beijing Key Laboratory for Cancer Invasion and Metastasis, Department of Oncology, Capital Medical University, Beijing, China.
Front Immunol. 2021 Oct 26;12:724276. doi: 10.3389/fimmu.2021.724276. eCollection 2021.
Natural killer (NK) cells are lymphocytes primarily involved in innate immunity and exhibit important functional properties in antimicrobial and antitumoral responses. Our previous work indicated that the enhancer of zeste homolog 2 (Ezh2) is a negative regulator of early NK cell differentiation and function through trimethylation of histone H3 lysine 27 (H3K27me3). Here, we deleted Ezh2 from immature NK cells and downstream progeny to explore its role in NK cell maturation by single-cell RNA sequencing (scRNA-seq). We identified six distinct NK stages based on the transcriptional signature during NK cell maturation. Conditional deletion of Ezh2 in NK cells resulted in a maturation trajectory toward NK cell arrest in CD11b SP stage 5, which was clustered with genes related to the activating function of NK cells. Mechanistically, we speculated that Ezh2 plays a critical role in NK development by activating AP-1 family gene expression independent of PRC2 function. Our results implied a novel role for the Ezh2-AP-1-Klrg1 axis in altering the NK cell maturation trajectory and NK cell-mediated cytotoxicity.
自然杀伤 (NK) 细胞是主要参与固有免疫的淋巴细胞，在抗微生物和抗肿瘤反应中表现出重要的功能特性。我们之前的工作表明，增强子的锌指蛋白 2（Ezh2）通过组蛋白 H3 赖氨酸 27（H3K27me3）的三甲基化，是早期 NK 细胞分化和功能的负调节剂。在这里，我们通过单细胞 RNA 测序（scRNA-seq）从未成熟的 NK 细胞及其下游祖细胞中删除 Ezh2，以探索其在 NK 细胞成熟中的作用。我们根据 NK 细胞成熟过程中的转录特征，确定了六个不同的 NK 阶段。在 NK 细胞中条件性删除 Ezh2 会导致 NK 细胞成熟轨迹停滞在 CD11b SP 阶段 5，该阶段与与 NK 细胞激活功能相关的基因聚类在一起。从机制上讲，我们推测 Ezh2 通过激活独立于 PRC2 功能的 AP-1 家族基因表达，在 NK 发育中发挥关键作用。我们的结果表明，Ezh2-AP-1-Klrg1 轴在改变 NK 细胞成熟轨迹和 NK 细胞介导的细胞毒性方面具有新的作用。
