Activation of natural killer (NK) cells with the cytokines interleukin-12 (IL-12), IL-15, and IL-18 induces their differentiation into memory-like (ML) NK cells; however, the underlying epigenetic and transcriptional mechanisms are unclear. By combining ATAC-seq, CITE-seq, and functional analyses, we discovered that IL-12/15/18 activation results in two main human NK fates: reprogramming into enriched memory-like (eML) NK cells or priming into effector conventional NK (effcNK) cells. eML NK cells had distinct transcriptional and epigenetic profiles and enhanced function, whereas effcNK cells resembled cytokine-primed cNK cells. Two transcriptionally discrete subsets of eML NK cells were also identified, eML-1 and eML-2, primarily arising from CD56 bright or CD56 dim mature NK cell subsets, respectively. Furthermore, these eML subsets were evident weeks after transfer of IL-12/15/18–activated NK cells into patients with cancer. Our findings demonstrate that NK cell activation with IL-12/15/18 results in previously unappreciated diverse cellular fates and identifies new strategies to enhance NK therapies.

中文翻译：

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细胞因子通过表观遗传重连和转录调控驱动记忆样 NK 细胞亚群的形成


用细胞因子白细胞介素 12 (IL-12)、IL-15 和 IL-18 激活自然杀伤 (NK) 细胞，诱导其分化为记忆样 (ML) NK 细胞；然而，潜在的表观遗传和转录机制尚不清楚。通过结合 ATAC-seq、CITE-seq 和功能分析，我们发现 IL-12/15/18 激活导致两种主要的人类 NK 命运：重编程为富集记忆样 (eML) NK 细胞或启动为效应器常规 NK （effcNK）细胞。 eML NK 细胞具有独特的转录和表观遗传特征以及增强的功能，而 effcNK 细胞类似于细胞因子引发的 cNK 细胞。还鉴定了 eML NK 细胞的两个转录离散子集：eML-1 和 eML-2，主要源自 CD56明亮的或CD56暗淡分别是成熟的 NK 细胞亚群。此外，这些 eML 子集在将 IL-12/15/18 激活的 NK 细胞转移到癌症患者体内几周后就变得明显。我们的研究结果表明，IL-12/15/18 激活 NK 细胞会导致以前未意识到的多种细胞命运，并确定了增强 NK 治疗的新策略。