Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Blood. 2010 Feb 11;115(6):1166-74. doi: 10.1182/blood-2009-09-245746. Epub 2009 Nov 10.
Expression of inhibitory killer cell immunoglobulin-like receptors (KIRs) specific for self-major histocompatibility complex (MHC) class I molecules provides an educational signal that generates functional natural killer (NK) cells. However, the effects of activating KIRs specific for self-MHC class I on NK-cell education remain elusive. Here, we provide evidence that the activating receptor KIR2DS1 tunes down the responsiveness of freshly isolated human NK cells to target cell stimulation in donors homozygous for human leukocyte antigen (HLA)-C2, the ligand of KIR2DS1. The tuning was apparent in KIR2DS1(+) NK cells lacking expression of inhibitory KIRs and CD94/NKG2A, as well as in KIR2DS1(+) NK cells coexpressing the inhibitory MHC class I-specific receptors CD94/NKG2A and KIR2DL3, but not KIR2DL1. However, the tuning of responsiveness was restricted to target cell recognition because KIR2DS1(+) NK cells responded well to stimulation with exogenous cytokines. Our results provide the first example of human NK-cell education by an activating KIR and suggest that the education of NK cells via activating KIRs is a mechanism to secure tolerance that complements education via inhibitory KIRs.
抑制性杀伤细胞免疫球蛋白样受体（KIR）对自身主要组织相容性复合体（MHC）I 类分子的表达提供了一个教育信号，从而产生功能性自然杀伤（NK）细胞。然而，针对自身 MHC I 类分子的激活型 KIR 对 NK 细胞教育的影响仍不清楚。在这里，我们提供的证据表明，激活受体 KIR2DS1 下调了 HLA-C2 纯合供体中新鲜分离的人类 NK 细胞对靶细胞刺激的反应性，HLA-C2 是 KIR2DS1 的配体。在缺乏抑制性 KIR 和 CD94/NKG2A 表达的 KIR2DS1(+)NK 细胞以及共表达抑制性 MHC I 特异性受体 CD94/NKG2A 和 KIR2DL3 的 KIR2DS1(+)NK 细胞中，均观察到这种调谐，但 KIR2DL1 则不然。然而，反应性的调谐仅限于靶细胞识别，因为 KIR2DS1(+)NK 细胞对细胞外细胞因子的刺激反应良好。我们的研究结果提供了第一个关于激活型 KIR 对人类 NK 细胞教育的例子，并表明通过激活型 KIR 对 NK 细胞的教育是一种确保与通过抑制型 KIR 教育相补充的耐受的机制。
