Adaptive features of natural killer (NK) cells have been reported in various species with different underlying mechanisms. It is unclear, however, which NK cell populations are capable of mounting antigen-specific recall responses and how such functions are regulated at the molecular level. Here, we identify and characterize a discrete population of CD49a⁺CD16⁻ NK cells in the human liver that displays increased epigenetic potential to elicit memory responses and has the functional properties to exert antigen-specific immunity in the skin as an effector site. Integrated chromatin-based epigenetic and transcriptomic profiling revealed unique characteristics of hepatic CD49a⁺CD16⁻ NK cells when compared with conventional CD49a⁻CD16⁺ NK cells, thereby defining active genomic regions and molecules underpinning distinct NK cell reactivity. In contrast to conventional NK cells, our results suggest that adaptive CD49a⁺CD16⁻ NK cells are able to bypass the KIR receptor-ligand system upon antigen-specific stimulation. Furthermore, these cells were highly migratory toward chemokine gradients expressed in epicutaneous patch test lesions as an effector site of adaptive immune responses in the skin. These results define pathways operative in human antigen-specific adaptive NK cells and provide a roadmap for harnessing this NK cell subset for specific therapeutic or prophylactic vaccine strategies.

据报道，自然杀伤 (NK) 细胞的适应性特征在不同物种中具有不同的潜在机制。然而，目前尚不清楚哪些 NK 细胞群能够产生抗原特异性回忆反应，以及如何在分子水平上调节此类功能。在这里，我们鉴定并表征了人类肝脏中CD49a ⁺ CD16 ^- NK 细胞的离散群体，这些细胞表现出增强的表观遗传潜力，可引发记忆反应，并具有在皮肤中作为效应位点发挥抗原特异性免疫的功能特性。与传统的CD49a ^- CD16 ^{+ NK 细胞相比，基于染色质的综合表观遗传和转录组分析揭示了肝 CD49a +} CD16 ^- NK 细胞的独特特征，从而定义了支持不同 NK 细胞反应性的活性基因组区域和分子。与传统的 NK 细胞相比，我们的结果表明，适应性 CD49a ⁺ CD16 ^- NK 细胞能够在抗原特异性刺激下绕过 KIR 受体-配体系统。此外，这些细胞高度迁移到表皮斑贴试验病变中表达的趋化因子梯度，作为皮肤中适应性免疫反应的效应位点。这些结果定义了人类抗原特异性适应性 NK 细胞的有效途径，并为利用该 NK 细胞亚群进行特定的治疗或预防性疫苗策略提供了路线图。