Inhibition of the MHC class II antigen presentation pathway by human cytomegalovirus.
Inhibition of the MHC class II antigen presentation pathway by human cytomegalovirus.
复制标题
人巨细胞病毒对 MHC II 类抗原呈递途径的抑制。
DOI：
10.1007/978-3-642-59421-2_7
复制
发表时间：
2002
影响因子：
--
通讯作者：
Hegde,NR
中科院分区：
文献类型：
--
作者：
Johnson,DC;Hegde,NR
人巨细胞病毒（HCMV）在免疫功能低下的个体中引起严重的疾病。正常情况下，抗hcmv免疫反应控制病毒从潜伏期重新激活后的复制。然而，像其他大型疱疹病毒一样，HCMV编码免疫逃避蛋白，允许病毒在一段时间内或在特定组织中复制，并在面对强大的宿主免疫时产生病毒后代。HCMV糖蛋白US2、US3、US6和US11均可抑制MHC I类抗原呈递途径的不同阶段，并可降低CD8+T淋巴细胞的识别。在这里，我们讨论了MHC II类抗原呈递途径的两种新型抑制剂，HCMV糖蛋白US2和US3。体外实验表明，US2和US3均能抑制外源蛋白抗原向CD4+T淋巴细胞的呈递。US2可降解MHC II类分子：HLA-DR-α和HLA-DM-α，以及I类重链（HC），但不影响DR-β或DM-β链。已经构建了US2的突变形式，可以结合DR-α和I类HC，但不会导致它们的降解，将结合步骤与降解之前的其他过程分开。我们还发现证据表明，us2诱导的I类和II类蛋白的降解涉及一种数量有限的细胞成分，而不是Sec61。与US2不同，US3结合新合成的II类α/β复合物，减少与不变链（II）的结合，并导致细胞中II类复合物的错定位。US3的表达减少了II类复合物在肽装载室和肽装载中的积累。由于US2和US3仅在hcmv感染的细胞内表达，这些病毒蛋白似乎已经进化到抑制内源性细胞内病毒抗原向抗hcmv CD4+T细胞的呈递。这与通常认为的MHC II类途径不同，MHC II类途径是外源性细胞外蛋白的呈现途径。这些蛋白的存在表明ii类介导的内源性抗原在信号病毒感染CD4+T细胞中的重要性。
Human cytomegalovirus (HCMV) causes serious disease in immunocompromised individuals. Normally, anti-HCMV immune response controls virus replication following reactivation from latency. However, HCMV, like other large herpesviruses, encodes immune evasion proteins that allow the virus to replicate, for a time or in specific tissues, and produce viral progeny in the face of robust host immunity. HCMV glycoproteins US2, US3, US6 and US11 all inhibit different stages of the MHC class I antigen presentation pathway and can reduce recognition by CD8+T lymphocytes. Here, we discuss two novel inhibitors of the MHC class II antigen presentation pathway, HCMV glycoproteins US2 and US3. Both US2 and US3 can inhibit presentation of exogenous protein antigens to CD4+T lymphocytes in in vitro assays. US2 causes degradation of MHC class II molecules: HLA-DR-α and HLA-DM-α, as well as class I heavy chain (HC), but does not affect DR-β or DM-β chains. Mutant forms of US2 have been constructed that can bind to DR-α and class I HC but do not cause their degradation, separating the binding step from other processes that precede degradation. We also found evidence that US2-induced degradation of class I and II proteins involves a cellular component, other than Sec61, that is limiting in quantity. Unlike US2, US3 binds newly synthesized class II α/β complexes, reducing the association with the invariant chain (Ii) and causing mislocalization of class II complexes in cells. US3 expression reduces accumulation of class II complexes in peptide-loading compartments and loading of peptides. Since US2 and US3 are expressed solely within HCMV-infected cells, it appears that these viral proteins have evolved to inhibit presentation of endogenous, intracellular viral antigens to anti-HCMV CD4+T cells. This is different from how the MHC class II pathway is normally viewed, as a pathway for presentation of exogenous, extracellular proteins. The existence of these proteins indicates the importance of class II-mediated presentation of endogenous antigens in signalling virus infection to CD4+T cells.