Quinn Laura L, Williams Luke R, White Claire, Forrest Calum, Zuo Jianmin, Rowe Martin
Institute of Immunology & Immunotherapy (III), College of Medical & Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
Institute of Immunology & Immunotherapy (III), College of Medical & Dental Sciences, University of Birmingham, Birmingham, United Kingdom
J Virol. 2015 Oct 14;90(1):356-67. doi: 10.1128/JVI.02183-15. Print 2016 Jan 1.
The ability of Epstein-Barr virus (EBV) to spread and persist in human populations relies on a balance between host immune responses and EBV immune evasion. CD8(+) cells specific for EBV late lytic cycle antigens show poor recognition of target cells compared to immediate early and early antigen-specific CD8(+) cells. This phenomenon is due in part to the early EBV protein BILF1, whose immunosuppressive activity increases with lytic cycle progression. However, published data suggest the existence of a hitherto unidentified immune evasion protein further enhancing protection against late EBV antigen-specific CD8(+) cells. We have now identified the late lytic BDLF3 gene as the missing link accounting for efficient evasion during the late lytic cycle. Interestingly, BDLF3 also contributes to evasion of CD4(+) cell responses to EBV. We report that BDLF3 downregulates expression of surface major histocompatibility complex (MHC) class I and class II molecules in the absence of any effect upon other surface molecules screened, including CD54 (ICAM-1) and CD71 (transferrin receptor). BDLF3 both enhanced internalization of surface MHC molecules and reduced the rate of their appearance at the cell surface. The reduced expression of surface MHC molecules correlated with functional protection against CD8(+) and CD4(+) T cell recognition. The molecular mechanism was identified as BDLF3-induced ubiquitination of MHC molecules and their subsequent downregulation in a proteasome-dependent manner.
Immune evasion is a necessary feature of viruses that establish lifelong persistent infections in the face of strong immune responses. EBV is an important human pathogen whose immune evasion mechanisms are only partly understood. Of the EBV immune evasion mechanisms identified to date, none could explain why CD8(+) T cell responses to late lytic cycle genes are so infrequent and, when present, recognize lytically infected target cells so poorly relative to CD8(+) T cells specific for early lytic cycle antigens. The present work identifies an additional immune evasion protein, BDLF3, that is expressed late in the lytic cycle and impairs CD8(+) T cell recognition by targeting cell surface MHC class I molecules for ubiquitination and proteasome-dependent downregulation. Interestingly, BDLF3 also targets MHC class II molecules to impair CD4(+) T cell recognition. BDLF3 is therefore a rare example of a viral protein that impairs both the MHC class I and class II antigen-presenting pathways.
爱泼斯坦-巴尔病毒（EBV）在人群中传播和持续存在的能力依赖于宿主免疫反应与EBV免疫逃逸之间的平衡。与针对即刻早期和早期抗原的CD8(+)细胞相比，针对EBV晚期裂解周期抗原的CD8(+)细胞对靶细胞的识别能力较差。这种现象部分归因于早期EBV蛋白BILF1，其免疫抑制活性随着裂解周期的进展而增加。然而，已发表的数据表明存在一种迄今尚未鉴定的免疫逃逸蛋白，它进一步增强了对晚期EBV抗原特异性CD8(+)细胞的保护作用。我们现已确定晚期裂解BDLF3基因是晚期裂解周期中有效逃逸的缺失环节。有趣的是，BDLF3也有助于逃避CD4(+)细胞对EBV的反应。我们报告称，BDLF3在对包括CD54（细胞间黏附分子-1）和CD71（转铁蛋白受体）在内的其他筛选表面分子无任何影响的情况下，下调表面主要组织相容性复合体（MHC）I类和II类分子的表达。BDLF3既增强了表面MHC分子的内化，又降低了它们在细胞表面出现的速率。表面MHC分子表达的降低与对CD8(+)和CD4(+) T细胞识别的功能保护相关。分子机制被确定为BDLF3诱导的MHC分子泛素化及其随后以蛋白酶体依赖方式的下调。
免疫逃逸是病毒在面对强烈免疫反应时建立终身持续感染的必要特征。EBV是一种重要的人类病原体，其免疫逃逸机制仅部分为人所知。在迄今为止确定的EBV免疫逃逸机制中，没有一种能够解释为什么CD8(+) T细胞对晚期裂解周期基因的反应如此罕见，以及当存在时，相对于针对早期裂解周期抗原的CD8(+) T细胞，对裂解感染的靶细胞的识别能力如此之差。目前的研究确定了一种额外的免疫逃逸蛋白BDLF3，它在裂解周期后期表达，并通过将细胞表面MHC I类分子靶向泛素化和蛋白酶体依赖的下调来损害CD8(+) T细胞的识别。有趣的是，BDLF3也靶向MHC II类分子以损害CD4(+) T细胞的识别。因此，BDLF3是一种罕见的病毒蛋白，它损害MHC I类和II类抗原呈递途径。
