Natural killer (NK) cells are innate effectors armed with cytotoxic and cytokine-secreting capacities whose spontaneous antitumor activity is key to numerous immunotherapeutic strategies. However, current mouse models fail to mirror the extensive immune system variation that exists in the human population which may impact on NK cell-based therapies. We performed a comprehensive profiling of NK cells in the Collaborative Cross (CC), a collection of novel recombinant inbred mouse strains whose genetic diversity matches that of humans, thereby providing a unique and highly diverse small animal model for the study of immune variation. We demonstrate that NK cells from CC strains displayed a breadth of phenotypic and functional variation reminiscent of that reported for humans with regards to cell numbers, key marker expression, and functional capacities. We took advantage of the vast genetic diversity of the CC and identified nine genomic loci through quantitative trait locus mapping driving these phenotypic variations. SNP haplotype patterns and variant effect analyses identified candidate genes associated with lung NK cell numbers, frequencies of CD94⁺ NK cells, and expression levels of NKp46. Thus, we demonstrate that the CC represents an outstanding resource to study NK cell diversity and its regulation by host genetics.

自然杀伤 (NK) 细胞是具有细胞毒性和细胞因子分泌能力的先天效应细胞，其自发抗肿瘤活性是众多免疫治疗策略的关键。然而，目前的小鼠模型未能反映人群中存在的广泛免疫系统变异，这可能会影响基于 NK 细胞的疗法。我们在 Collaborative Cross (CC) 中对 NK 细胞进行了全面分析，CC 是一组新的重组近交小鼠品系，其遗传多样性与人类相匹配，从而为研究免疫变异提供了独特且高度多样化的小动物模型。我们证明来自 CC 菌株的 NK 细胞显示出广泛的表型和功能变异，这让人想起在细胞数量、关键标记表达、和功能能力。我们利用 CC 的巨大遗传多样性，并通过驱动这些表型变异的数量性状基因座定位确定了 9 个基因组位点。SNP 单倍型模式和变异效应分析确定了与肺 NK 细胞数量、CD94 频率相关的候选基因⁺ NK 细胞和 NKp46 的表达水平。因此，我们证明 CC 是研究 NK 细胞多样性及其受宿主遗传学调控的优秀资源。