Pinto Amelia K, Jamieson Amanda M, Raulet David H, Hill Ann B
Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239, USA.
J Virol. 2007 Nov;81(22):12564-71. doi: 10.1128/JVI.01328-07. Epub 2007 Sep 12.
Three proteins encoded by murine cytomegalovirus (MCMV) -- gp34, encoded by m04 (m04/gp34), gp48, encoded by m06 (m06/gp48), and gp40, encoded by m152 (m152/gp40) -- act together to powerfully impact the ability of primed cytotoxic CD8 T lymphocytes (CTL) to kill virus-infected cells. Of these three, the impact of m152/gp40 on CTL lysis appears greater than would be expected based on its impact on cell surface major histocompatibility complex (MHC) class I. In addition to MHC class I, m152/gp40 also downregulates the RAE-1 family of NKG2D ligands, which can provide costimulation for CD8 T cells. We hypothesized that m152/gp40 may impact CTL lysis so profoundly because it inhibits both antigen presentation and NKG2D-mediated costimulation. We therefore tested the extent to which m152/gp40's ability to inhibit CTL lysis of MCMV-infected cells could be accounted for by its inhibition of NKG2D signaling. As was predictable from the results reported in the literature, NKG2D ligands were not detected by NKG2D tetramer staining of cells infected with wild-type MCMV, whereas those infected with MCMV lacking m152/gp40 displayed measurable levels of the NKG2D ligand. To determine whether NKG2D signaling contributed to the ability of CTL to lyse these cells, we used a blocking anti-NKG2D antibody. Blocking NKG2D signaling did affect the killing of MCMV-infected cells for some epitopes. However, for all epitopes, the impact of m152/gp40 on CTL lysis was much greater than the impact of inhibition of NKG2D signaling. We conclude that the downregulation of NKG2D ligands by MCMV makes only a small contribution to the impact of m152/gp40 on CTL lysis and only for a small subset of CTL.
鼠巨细胞病毒（MCMV）编码的三种蛋白质——由m04编码的gp34（m04/gp34）、由m06编码的gp48（m06/gp48）和由m152编码的gp40（m152/gp40）——共同作用，对致敏细胞毒性CD8 T淋巴细胞（CTL）杀伤病毒感染细胞的能力产生强大影响。在这三种蛋白质中，m152/gp40对CTL裂解的影响似乎比基于其对细胞表面主要组织相容性复合体（MHC）I类的影响所预期的更大。除了MHC I类，m152/gp40还下调NKG2D配体的RAE - 1家族，而NKG2D配体可为CD8 T细胞提供共刺激。我们推测m152/gp40可能对CTL裂解有如此深刻的影响，是因为它既抑制抗原呈递又抑制NKG2D介导的共刺激。因此，我们测试了m152/gp40抑制MCMV感染细胞的CTL裂解能力在多大程度上可归因于其对NKG2D信号传导的抑制。正如从文献报道的结果中可预测的那样，野生型MCMV感染的细胞经NKG2D四聚体染色未检测到NKG2D配体，但感染缺乏m152/gp40的MCMV的细胞显示出可测量水平的NKG2D配体。为了确定NKG2D信号传导是否有助于CTL裂解这些细胞的能力，我们使用了阻断性抗NKG2D抗体。阻断NKG2D信号传导确实影响了某些表位的MCMV感染细胞的杀伤。然而，对于所有表位，m152/gp40对CTL裂解的影响远大于抑制NKG2D信号传导的影响。我们得出结论，MCMV对NKG2D配体的下调对m152/gp40对CTL裂解的影响贡献很小，且仅对一小部分CTL有影响。
