Differential effects of US2, US6 and US11 human cytomegalovirus proteins on HLA class Ia and HLA-E expression:: impact on target susceptibility to NK cell subsets
Differential effects of US2, US6 and US11 human cytomegalovirus proteins on HLA class Ia and HLA-E expression:: impact on target susceptibility to NK cell subsets
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DOI：
10.1002/eji.200324182
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发表时间：
2003-10-01
影响因子：
5.4
通讯作者：
López-Botet, M
中科院分区：
文献类型：
--
作者：
Llano, M;Gumá, M;López-Botet, M
我们在诱导表达系统中比较了US 2、US 6和US 11人巨细胞病毒（HCMV）蛋白对HLA-E和HLA Ia类表面表达的个体效应，同时评估了它们对NK细胞克隆靶易感性的影响。为此，将RPMI 8866 B淋巴瘤细胞系（HLA-A2、HLA-A3、HLA-B7、HLA-Cw 7、HLA-E-R、HLA-E-G）与蜕皮激素受体以及在蜕皮激素诱导型启动子控制下的US序列稳定共转染。通过用Ponasterone A孵育转染子来开启病毒蛋白的生物合成。US 6下调了所有I类分子的表达，阻碍了对由CD 94/NKG 2A、KIR 2DL 2和/或CD 85 j（ILT 2或LIR-1）抑制性受体控制的NK细胞克隆的靶抗性。相比之下，US 11降低了Ia类分子的表面水平，但保留了HLA-E;这使得US 11（+）细胞对KIR 2DL 2和/或CD 85 j控制下的NK克隆敏感，而它们对CD 94/NKG 2A（+）KIR 2DL 2 ㈠效应细胞的抗性得以维持。US 2也保留了HLA-E表达，但选择性靶向Ia类分子;事实上，HLA-A和HLA-C同种异型被下调，而HLA-B7保持不变。US 2（+）靶标对KIR 2DL 2（+）细胞变得敏感，但对CD 94/NKG 2A（+）CD 85 j NK克隆保持抗性。US蛋白对HLA Ia类和HLA-E的不同作用可能反映了HCMV对抗NK介导的监视的进化适应。
We compared in an inducible expression system the individual effect of US2, US6 and US11 human cytomegalovirus (HCMV) proteins on HLA-E and HLA class la surface expression, assessing in parallel their influence on target susceptibility to NK cell clones. To this end, the RPMI 8866 B lymphoma cell line (HLA-A2, HLA-A3, HLA-B7, HLA-Cw7, HLA-E-R, HLA-E-G) was stably cotransfected with the ecdysone receptor, together with the US sequences under the control of an ecdysone-inducible promoter. Biosynthesis of viral proteins was turned on by incubating transfectants with Ponasterone A. US6 down-regulated expression of all class I molecules, hampering target resistance to NK cell clones controlled by the CD94/ NKG2A, KIR2DL2 and/or CD85j (ILT2 or LIR-1) inhibitory receptors. By contrast, US11 reduced the surface levels of class la molecules but preserved HLA-E; this rendered US11(+) cells sensitive to NK clones under the control of KIR2DL2 and/or CD85j, while their resistance to CD94/NKG2A(+)KIR2DL2(-) effector cells was maintained. US2 preserved as well HLA-E expression but selectively targeted class la molecules; in fact, HLA-A and HLA-C allotypes were down-modulated whereas HLA-B7 remained unaltered. US2(+) targets became sensitive to KIR2DL2(+) cells but remained resistant to CD94/NKG2A(+)CD85j NK clones. The differential effects of US proteins on HLA class la and HLA-E likely reflect the evolutionary adaptation of HCMV to counteract NK-mediated surveillance.