Department of Immunology and Immunotherapy.
Department of Oncological Sciences.
JCI Insight. 2024 Nov 8;9(21):e185687. doi: 10.1172/jci.insight.185687.
Natural killer (NK) cells respond to diseased and allogeneic cells through NKG2A/HLA-E or killer cell immunoglobulin-like receptor (KIR)/HLA-ABC interactions. Correlations between HLA/KIR disparities and kidney transplant pathology suggest an antibody-independent pathogenic role for NK cells in transplantation, but the mechanisms remain unclear. Using CyTOF to characterize recipient peripheral NK cell phenotypes and function, we observed diverse NK cell subsets among participants who responded heterogeneously to allo-stimulators. NKG2A+KIR+ NK cells responded more vigorously than other subsets, and this heightened response persisted after kidney transplantation despite immunosuppression. In test and validation sets from 2 clinical trials, pretransplant donor-induced release of cytotoxicity mediator Ksp37 by NKG2A+ NK cells correlated with reduced long-term allograft function. Separate analyses showed that Ksp37 gene expression in allograft biopsies lacking histological rejection correlated with death-censored graft loss. Our findings support an antibody-independent role for NK cells in transplant injury and support further testing of pretransplant, donor-reactive, NK cell-produced Ksp37 as a risk-assessing, transplantation biomarker.
自然杀伤 (NK) 细胞通过 NKG2A/HLA-E 或杀伤细胞免疫球蛋白样受体 (KIR)/HLA-ABC 相互作用来响应病变和同种异体细胞。HLA/KIR 差异与肾移植病理学之间的相关性表明 NK 细胞在移植中具有抗体非依赖性的致病作用，但机制仍不清楚。使用 CyTOF 来描述受体外周 NK 细胞表型和功能，我们观察到对同种刺激剂反应不同的参与者之间存在多种 NK 细胞亚群。与其他亚群相比，NKG2A+KIR+NK 细胞的反应更为强烈，尽管存在免疫抑制，但这种增强的反应在肾移植后仍然存在。在来自 2 项临床试验的测试和验证集中，移植前供体诱导的 NKG2A+NK 细胞释放细胞毒性介质 Ksp37 与长期移植物功能降低相关。单独的分析表明，在没有组织学排斥的移植活检中，Ksp37 基因表达与死亡相关的移植物丢失相关。我们的研究结果支持 NK 细胞在移植损伤中具有抗体非依赖性作用，并支持进一步测试移植前、供体反应性、NK 细胞产生的 Ksp37 作为风险评估、移植生物标志物。
