自然杀伤（NK）复合物（NKC）包含多个基因，如KLRC1（编码NKG2A）和KLRK1（编码NKG2D），这些基因对NK细胞功能的调节至关重要。我们旨在确定NKC单倍型对NK细胞库和功能的影响程度，并且这样的基因变体是否影响白血病（AML）基于IL-2免疫疗法的结果。使用TaqMan-Allelic鉴定方法确定了NKG2D rs1049174和NKG2A rs1983526的基因型。为了解析单核苷酸多态性（SNP）对NK细胞功能的影响，我们使用CRISPR工程化了高度依赖NKG2D的方式杀死K562细胞系。使用流式细胞术测定NK细胞的脱颗粒化、细胞内细胞因子产生和细胞毒性。在接受免疫疗法的AML患者中，NKG2A基因变体rs1983526与白血病无复发生存和总生存有关。我们观察到，高细胞毒性的NKG2D变体个体的上优NK脱颗粒化可以解释为存在一个更大的、高反应的NKG2A阳性亚群。值得注意的是，携带有有利于编码NKG2A的等位基因纯合的捐赠者的NK细胞在与白血病细胞挑战时产生更强的细胞因子反应，而这个基因型的AML患者的NK细胞在组脱嗪双氯化物/IL-2免疫疗法期间表现出较高的粒酶B积累。此外，在AML患者中，NKG2A SNP定义了一组具有明显有利结果的HLA-B-21 TT患者亚群。研究结果表明，NKG2A基因中的双形性与增强的NK细胞效应物功能和AML的IL-2免疫疗法的改善结果相关。©作者（或其雇主）2023年。根据CC BY发布的BMJ。

The natural killer (NK) complex (NKC) harbors multiple genes such as KLRC1 (encoding NKG2A) and KLRK1 (encoding NKG2D) that are central to regulation of NK cell function. We aimed at determining to what extent NKC haplotypes impact on NK cell repertoire and function, and whether such gene variants impact on outcome of IL-2-based immunotherapy in acute myeloid leukemia (AML).Genotype status of NKG2D rs1049174 and NKG2A rs1983526 was determined using the TaqMan-Allelic discrimination approach. To dissect the impact of single nucloetide polymorphim (SNP) on NK cell function, we engineered the K562 cell line with CRISPR to be killed in a highly NKG2D-dependent fashion. NK cells were assayed for degranulation, intracellular cytokine production and cytotoxicity using flow cytometry.In AML patients receiving immunotherapy, the NKG2A gene variant, rs1983526, was associated with superior leukemia-free survival and overall survival. We observed that superior NK degranulation from individuals with the high-cytotoxicity NKG2D variant was explained by presence of a larger, highly responsive NKG2A+ subset. Notably, NK cells from donors homozygous for a favorable allele encoding NKG2A mounted stronger cytokine responses when challenged with leukemic cells, and NK cells from AML patients with this genotype displayed higher accumulation of granzyme B during histamine dihydrochloride/IL-2 immunotherapy. Additionally, among AML patients, the NKG2A SNP defined a subset of patients with HLA-B-21 TT with a strikingly favorable outcome.The study results imply that a dimorphism in the NKG2A gene is associated with enhanced NK cell effector function and improved outcome of IL-2-based immunotherapy in AML.© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.