Laboratory of Immunogenetics and Allergology, Public Research Center for Health, L-1526 Luxembourg, Luxembourg;
J Immunol. 2014 Mar 15;192(6):2602-10. doi: 10.4049/jimmunol.1302843. Epub 2014 Feb 19.
The interaction between clonally distributed inhibitory receptors and their activating counterparts on NK cells and HLA class I molecules defines NK cell functions, but the role of HLA class I ligands in the acquisition of their receptors during NK development is still unclear. Although some studies demonstrated that HLA-C affects the expression of killer Ig-like receptors (KIR), other studies showed that NK cells acquire their KIR repertoire in a stochastic manner. Only when infected with human CMV is an expansion of self-specific KIR(+) NKG2C(+) NK cells detected. To gain more insight into this question, we compared the coexpression of different KIR molecules, NKG2A, CD8, and CD57, on NK cells in healthy donors and seven patients with deficient HLA class I expression due to mutations in one of the TAP genes. Our results show a correlation between the presence/absence of HLA class I molecules and the coexpression of their receptors. In an HLA class I low-expression context, an increase in KIR molecules' coexpression is detected on the NKG2A(+) CD8(+) subset. In functional assays, hyporesponsiveness was observed for TAP-deficient NK cells derived from four patients. In contrast, NK cells from patient five were functional, whereas CD107a(+) and IFN-γ(+) CD56(dim) NK cells presented a different pattern of HLA class I receptors compared with healthy donors. Taken together, our results provide strong evidence for the role of HLA class I molecules in NK cell maturation and KIR repertoire acquisition.
抑制性受体和其在 NK 细胞上的激活配体与 HLA Ⅰ类分子的相互作用决定了 NK 细胞的功能，但 HLA Ⅰ类分子配体在 NK 细胞发育过程中获得其受体的作用尚不清楚。虽然一些研究表明 HLA-C 影响杀伤免疫球蛋白样受体（KIR）的表达，但其他研究表明 NK 细胞以随机的方式获得其 KIR 库。只有在感染人类巨细胞病毒（CMV）时，才会检测到自我特异性 KIR(+)NKG2C(+) NK 细胞的扩增。为了更深入地了解这个问题，我们比较了健康供者和七位因 TAP 基因之一突变而 HLA Ⅰ类分子表达缺陷的患者 NK 细胞上不同 KIR 分子、NKG2A、CD8 和 CD57 的共表达。我们的结果显示 HLA Ⅰ类分子的存在/缺失与它们的受体的共表达之间存在相关性。在 HLA Ⅰ类分子低表达的情况下，在 NKG2A(+)CD8(+)亚群上检测到 KIR 分子共表达增加。在功能测定中，来自四位患者的 TAP 缺陷 NK 细胞表现出低反应性。相比之下，来自患者五的 NK 细胞是功能性的，而 CD107a(+)和 IFN-γ(+)CD56(dim) NK 细胞与健康供者相比呈现出不同的 HLA Ⅰ类受体模式。总之，我们的结果为 HLA Ⅰ类分子在 NK 细胞成熟和 KIR 库获得中的作用提供了有力的证据。
