Prod'homme Virginie, Griffin Cora, Aicheler Rebecca J, Wang Eddie C Y, McSharry Brian P, Rickards Carole R, Stanton Richard J, Borysiewicz Leszek K, López-Botet Miguel, Wilkinson Gavin W G, Tomasec Peter
Department of Medical Microbiology, Cardiff University, Heath Park, Cardiff, Wales, UK.
J Immunol. 2007 Apr 1;178(7):4473-81. doi: 10.4049/jimmunol.178.7.4473.
The inhibitory leukocyte Ig-like receptor 1 (LIR-1, also known as ILT2, CD85j, or LILRB1) was identified by its high affinity for the human CMV (HCMV) MHC class I homolog gpUL18. The role of this LIR-1-gpUL18 interaction in modulating NK recognition during HCMV infection has previously not been clearly defined. In this study, LIR-1(+) NKL cell-mediated cytotoxicity was shown to be inhibited by transduction of targets with a replication-deficient adenovirus vector encoding UL18 (RAd-UL18). Fibroblasts infected with an HCMV UL18 mutant (DeltaUL18) also exhibited enhanced susceptibility to NKL killing relative to cells infected with the parental virus. In additional cytolysis assays, UL18-mediated protection was also evident in the context of adenovirus vector transduction and HCMV infection of autologous fibroblast targets using IFN-alpha-activated NK bulk cultures derived from a donor with a high frequency of LIR-1(+) NK cells. A single LIR-1(high) NK clone derived from this donor was inhibited by UL18, while 3 of 24 clones were activated. CD107 mobilization assays revealed that LIR-1(+) NK cells were consistently inhibited by UL18 in all tested donors, but this effect was often masked in the global response by UL18-mediated activation of a subset of LIR-1(-) NK cells. Although Ab-blocking experiments support UL18 inhibition being induced by a direct interaction with LIR-1, the UL18-mediated activation is LIR-1 independent.
抑制性白细胞免疫球蛋白样受体1（LIR-1，也称为ILT2、CD85j或LILRB1）因其对人巨细胞病毒（HCMV）MHC I类同源物gpUL18具有高亲和力而被鉴定出来。此前，这种LIR-1与gpUL18的相互作用在HCMV感染期间调节自然杀伤细胞（NK）识别中的作用尚未明确界定。在本研究中，编码UL18的复制缺陷型腺病毒载体（RAd-UL18）转导靶细胞后，可抑制LIR-1(+) NKL细胞介导的细胞毒性。与感染亲本病毒的细胞相比，感染HCMV UL18突变体（DeltaUL18）的成纤维细胞对NKL杀伤的敏感性也增强。在其他细胞溶解试验中，使用来自LIR-1(+) NK细胞频率高的供体的经干扰素-α激活的NK大量培养物，在腺病毒载体转导和自体成纤维细胞靶细胞的HCMV感染的背景下，UL18介导的保护作用也很明显。从该供体获得的单个LIR-1(高) NK克隆被UL18抑制，而24个克隆中有3个被激活。CD107动员试验表明，在所有测试的供体中，LIR-1(+) NK细胞始终被UL18抑制，但这种效应在整体反应中常常被UL18介导的一部分LIR-1(-) NK细胞的激活所掩盖。尽管抗体阻断实验支持UL18抑制是由与LIR-1的直接相互作用诱导的，但UL18介导的激活不依赖于LIR-1。
