Pinto Amelia K, Munks Michael W, Koszinowski Ulrich H, Hill Ann B
Oregon Health and Science University, Molecular Microbiology and Immunology, Portland, OR 97239, USA.
J Immunol. 2006 Sep 1;177(5):3225-34. doi: 10.4049/jimmunol.177.5.3225.
Murine CMV (MCMV) encodes three viral genes that interfere with Ag presentation (VIPRs) to CD8 T cells, m04, m06, and m152. Because the functional impact of these genes during normal infection of C57BL/6 mice is surprisingly modest, we wanted to determine whether the VIPRs are equally effective against the entire spectrum of H-2(b)-restricted CD8 T cell epitopes. We also wanted to understand how the VIPRs interact at a functional level. To address these questions, we used a panel of MCMV mutants lacking each VIPR in all possible combinations, and CTL specific for 15 H-2(b)-restricted MCMV epitopes. Only expression of all three MCMV VIPRs completely inhibited killing by CTL specific for all 15 epitopes, but removal of any one VIPR enabled lysis by at least some CTL. The dominant interaction between the VIPRs was cooperation: m06 increased the inhibition of lysis achieved by either m152 or m04. However, for 1 of 15 epitopes m04 functionally antagonized m152. There was little differential impact of any of the VIPRs on K(b) vs D(b), but a surprising degree of differential impact of the three VIPRs for different epitopes. These epitope-specific differences did not correlate with functional avidity, or with timing of VIPR expression in relation to Ag expression in the virus replication cycle. Although questions remain about the molecular mechanism and in vivo role of these genes, we conclude that the coordinated function of MCMV's three VIPRs results in a powerful inhibition of lysis of infected cells by CD8 T cells.
小鼠巨细胞病毒（MCMV）编码三种干扰向CD8 T细胞呈递抗原（VIPR）的病毒基因，即m04、m06和m152。由于这些基因在C57BL/6小鼠正常感染过程中的功能影响出人意料地轻微，我们想确定这些VIPR对整个H-2(b)限制性CD8 T细胞表位谱是否同样有效。我们还想了解这些VIPR在功能水平上是如何相互作用的。为了解决这些问题，我们使用了一组以所有可能组合缺失每种VIPR的MCMV突变体，以及针对15种H-2(b)限制性MCMV表位的CTL。只有所有三种MCMV VIPR的表达完全抑制了针对所有15个表位的CTL的杀伤作用，但去除任何一种VIPR至少能使一些CTL进行裂解。VIPR之间的主要相互作用是协同作用：m06增强了m152或m04对裂解的抑制作用。然而，对于15个表位中的1个，m04在功能上拮抗m152。任何一种VIPR对K(b)与D(b)的影响几乎没有差异，但三种VIPR对不同表位的影响程度惊人。这些表位特异性差异与功能亲和力或病毒复制周期中VIPR表达相对于抗原表达的时间无关。尽管关于这些基因的分子机制和体内作用仍有问题，但我们得出结论，MCMV的三种VIPR的协同功能导致对CD8 T细胞裂解感染细胞的有力抑制。
