Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, Hiroshima, Japan.
Hum Immunol. 2012 Jun;73(6):686-91. doi: 10.1016/j.humimm.2012.03.003. Epub 2012 Apr 13.
NKG2D is a primary activating receptor that triggers cell-mediated cytotoxicity in NK cells against tumor and virus-infected cells. We previously identified the NKG2D haplotypes in the natural killer gene complex region on chromosome 12p. Two major haplotype alleles, LNK1 and HNK1, were closely related to low and high natural cytotoxic activity phenotypes, respectively. Furthermore, the haplotype of HNK1/HNK1 has revealed a decreased risk of cancer compared with LNK1/LNK1. In the present study, using flow cytometry, we evaluated the functional effects of NKG2D haplotypes and five htSNPs in terms of the cell-surface expression of NKG2D protein on NK and CD8 T cells of peripheral blood among 732 atomic-bomb survivors. NKG2D expression on NK cells showed significant increases, in the order of LNK1/LNK1, LNK1/HNK1 and HNK1/HNK1 haplotypes (p for trend=0.003), or with major homozygous, heterozygous, and minor homozygous genotypes for individual htSNPs (p for trend=0.02-0.003). The same trend was observed for NKG2D expression on CD8 T cells. Our findings indicate that the NKG2D haplotypes are associated with the expression levels of NKG2D protein on NK and CD8 T cells, resulting in inter-individual variations in human cytotoxic response.
NKG2D 是一种主要的激活受体，可触发 NK 细胞对肿瘤和病毒感染细胞的细胞介导的细胞毒性。我们之前在染色体 12p 上的自然杀伤基因复合物区域中鉴定了 NKG2D 单倍型。两种主要的单倍型等位基因 LNK1 和 HNK1 分别与低和高自然细胞毒性活性表型密切相关。此外，与 LNK1/LNK1 相比，HNK1/HNK1 单倍型显示出降低的癌症风险。在本研究中，我们使用流式细胞术评估了 NKG2D 单倍型和五个 htSNPs 的功能影响，涉及外周血 NK 和 CD8 T 细胞表面 NKG2D 蛋白的表达，在 732 名原子弹幸存者中。NK 细胞上的 NKG2D 表达呈显著增加趋势，依次为 LNK1/LNK1、LNK1/HNK1 和 HNK1/HNK1 单倍型（趋势检验 p=0.003），或与个体 htSNPs 的主要纯合子、杂合子和次要纯合子基因型相关（趋势检验 p=0.02-0.003）。在 CD8 T 细胞上也观察到相同的趋势。我们的研究结果表明，NKG2D 单倍型与 NK 和 CD8 T 细胞上 NKG2D 蛋白的表达水平相关，导致人类细胞毒性反应的个体间差异。
