Kim Sungjin, Sunwoo John B, Yang Liping, Choi Taewoong, Song Yun-Jeong, French Anthony R, Vlahiotis Anna, Piccirillo Jay F, Cella Marina, Colonna Marco, Mohanakumar Thalachallour, Hsu Katharine C, Dupont Bo, Yokoyama Wayne M
Howard Hughes Medical Institute, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
Proc Natl Acad Sci U S A. 2008 Feb 26;105(8):3053-8. doi: 10.1073/pnas.0712229105. Epub 2008 Feb 19.
Epidemiological studies have associated certain human disease outcomes with particular killer cell Ig-like receptor (KIR) and HLA genotypes. However, the functional explanation for these associations is poorly understood, because the KIRs were initially described as natural killer (NK) cell inhibitory receptors with specificity for HLA molecules on their cellular targets. Yet resolution of infections is often associated with genotypic pairing of inhibitory KIRs with their cognate HLA ligands. Recent studies in mice indicate a second role for MHC-specific inhibitory receptors, i.e., self-MHC recognition confers functional competence on the NK cell to be triggered through their activation receptors, a process termed licensing. As a result, licensed NK cells with self-MHC-specific receptors are more readily activated as compared with unlicensed NK cells without self-MHC-specific receptors. Such results predict that human NK cells may undergo a similar process. Here, we examined the human NK cell subset expressing KIR3DL1, the only known KIR specific for HLA-Bw4 alleles. The KIR3DL1(+) subset in normal donors with two HLA-B-Bw4 genes displayed increased responsiveness to tumor stimulation compared with the KIR3DL1(+) subset from individuals with only one or no Bw4 genes. By contrast, NK cells lacking KIR3DL1 showed no differences. Therefore, these data indicate that particular KIR and HLA alleles are associated with more responsive NK cells, strongly suggesting that human NK cells are also subjected to NK cell licensing, and providing a potential functional explanation for the influence of KIR and HLA genes in disease as well as interindividual differences in NK cell potency.
流行病学研究已将某些人类疾病结局与特定的杀伤细胞免疫球蛋白样受体（KIR）和HLA基因型联系起来。然而，对于这些关联的功能解释却知之甚少，因为KIR最初被描述为对其细胞靶标上的HLA分子具有特异性的自然杀伤（NK）细胞抑制性受体。然而，感染的解决通常与抑制性KIR与其同源HLA配体的基因型配对有关。最近在小鼠中的研究表明，MHC特异性抑制性受体还有第二个作用，即自身MHC识别赋予NK细胞通过其激活受体被触发的功能能力，这一过程称为许可。因此，与没有自身MHC特异性受体的未许可NK细胞相比，具有自身MHC特异性受体的许可NK细胞更容易被激活。这些结果预测人类NK细胞可能经历类似的过程。在这里，我们研究了表达KIR3DL1的人类NK细胞亚群，KIR3DL1是唯一已知的对HLA - Bw4等位基因具有特异性的KIR。与只有一个或没有Bw4基因的个体的KIR3DL1(+)亚群相比，具有两个HLA - B - Bw4基因的正常供体中的KIR3DL1(+)亚群对肿瘤刺激的反应性增加。相比之下，缺乏KIR3DL1的NK细胞没有差异。因此，这些数据表明特定的KIR和HLA等位基因与反应性更强的NK细胞相关，强烈提示人类NK细胞也经历NK细胞许可，并为KIR和HLA基因在疾病中的影响以及NK细胞效能的个体差异提供了潜在的功能解释。
