Abstract：
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 CD56bright or CD56dim 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.
摘要：
细胞因子白细胞介素12（IL-12）激活自然杀伤（NK）细胞，IL-15和IL-18诱导它们分化成记忆样（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细胞:重编程为富集的记忆样(eML)NK细胞或引发效应常规NK(effcNK)细胞。EMLNK细胞具有不同的转录和表观遗传谱，并且功能增强，而effcNK细胞类似于细胞因子引发的cNK细胞。还鉴定了两个转录上离散的eMLNK细胞亚群，eML-1和eML-2，主要来自CD56bright或CD56dim成熟NK细胞亚群，分别。此外，这些eML亚群在IL-12/15/18激活的NK细胞转移至癌症患者后数周出现.我们的发现表明，IL-12/15/18的NK细胞活化导致以前未被重视的不同细胞命运，并确定了增强NK治疗的新策略。
