Natural killer (NK) cells are innate lymphoid cells (ILCs) contributing to immune responses to microbes and tumors. Historically, their classification hinged on a limited array of surface protein markers. Here, we used single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to dissect the heterogeneity of NK cells. We identified three prominent NK cell subsets in healthy human blood: NK1, NK2 and NK3, further differentiated into six distinct subgroups. Our findings delineate the molecular characteristics, key transcription factors, biological functions, metabolic traits and cytokine responses of each subgroup. These data also suggest two separate ontogenetic origins for NK cells, leading to divergent transcriptional trajectories. Furthermore, we analyzed the distribution of NK cell subsets in the lung, tonsils and intraepithelial lymphocytes isolated from healthy individuals and in 22 tumor types. This standardized terminology aims at fostering clarity and consistency in future research, thereby improving cross-study comparisons.

自然杀伤 (NK) 细胞是先天性淋巴细胞 (ILC)，有助于对微生物和肿瘤的免疫反应。从历史上看，它们的分类取决于有限的表面蛋白标记。在这里，我们使用单细胞 RNA 测序 (scRNA-seq) 和通过测序对转录组和表位进行细胞索引 (CITE-seq) 来剖析 NK 细胞的异质性。我们在健康人体血液中鉴定出三个重要的 NK 细胞亚群：NK1、NK2 和 NK3，并进一步分化为六个不同的亚群。我们的研究结果描述了每个亚组的分子特征、关键转录因子、生物学功能、代谢特征和细胞因子反应。这些数据还表明 NK 细胞有两个不同的个体发育起源，导致不同的转录轨迹。此外，我们分析了从健康个体和 22 种肿瘤类型中分离出的肺、扁桃体和上皮内淋巴细胞中 NK 细胞亚群的分布。这一标准化术语旨在促进未来研究的清晰度和一致性，从而改善交叉研究比较。