Cooperation between Epstein-Barr virus immune evasion proteins spreads protection from CD8+ T cell recognition across all three phases of the lytic cycle.
Cooperation between Epstein-Barr virus immune evasion proteins spreads protection from CD8+ T cell recognition across all three phases of the lytic cycle.
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DOI：
10.1371/journal.ppat.1004322
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发表时间：
2014-08
期刊：
影响因子：
6.7
通讯作者：
Rowe M
中科院分区：
文献类型：
--
作者：
Quinn LL;Zuo J;Abbott RJ;Shannon-Lowe C;Tierney RJ;Hislop AD;Rowe M
CD 8 + T细胞对EB病毒（EBV）裂解周期表达的抗原的应答显示出免疫优势的层次，其中对立即早期（IE）和一些早期（E）抗原的表位的应答比对晚期（L）表达抗原的表位的应答更频繁地观察到。有人提出，这种与抗原提呈的阶段特异性效率相关的层次结构可能是由于病毒免疫逃避基因的影响。至少三种EBV编码的基因BNLF 2a、BGLF 5和BILF 1具有抑制CD 8 + T细胞表位的加工和呈递的潜力。在这里，我们研究了这些基因的相对贡献调制的CD 8 + T细胞识别EBV裂解抗原表达在不同阶段的复制周期的EBV转化的B细胞（LCL），自发地重新激活裂解周期。选择性shRNA介导的BNLF 2a表达敲低导致CD 8 + T细胞更有效地识别立即早期（IE）和早期（E）衍生的表位，而BILF 1敲低增加了对E和晚期（L）表达抗原表位的识别。与先前在EBV阴性模型细胞系中的异位表达研究所预测的相反，在LCL中，shRNA介导的BGLF 5表达的抑制仅显示出在裂解周期的任何阶段中表达的表位的识别的适度增加（如果有的话）。这些数据表明，虽然BNLF 2a干扰抗原呈递，随着裂解周期的进展效率降低（IE>E>>L），BILF 1的干扰随着裂解周期的进展而增加（IE<E<<L）。此外，双敲低实验显示BILF 1和BNLF 2a协同作用以进一步抑制L表位的抗原呈递。总之，这些数据首先表明哪些潜在的免疫逃避功能实际上与裂解病毒复制相关，其次确定裂解周期阶段特异性效应，这些效应提供了对CD 8 + T细胞对EBV裂解抗原应答的免疫显性模式的机制性见解。爱泼斯坦巴尔病毒（EBV）是一种致癌疱疹病毒，在大多数人中感染并无症状持续存在。在免疫功能正常的个体中，面对强大的抗病毒CD 8 + T细胞应答，EBV作为终身感染与其宿主共存。这种免疫应答的逃避被认为部分是由于某些EBV编码的蛋白质在裂解周期复制期间表达的免疫调节机制。三种这样的蛋白质（BNLF 2a、BGLF 5和BILF 1）已被生物化学鉴定为能够干扰HLA-I类抗原呈递。在这项研究中，我们研究了这些蛋白质的背景下，EBV感染的细胞在裂解周期，其功能识别EBV病毒特异性的CD 8 + T细胞。揭示了EBV生物学的一个新特征;逃避蛋白在裂解周期的不同阶段产生最佳的时间保护，而不是表现出简单的冗余。在EB病毒感染的细胞进入溶解周期后，BNLF 2a立即强烈抑制CD 8 + T细胞识别，随着进入溶解周期的后期阶段，其影响逐渐减弱。相反，BILF 1主要在裂解周期的晚期强烈抑制识别。出乎意料的是，尽管BGLF 5具有良好的分子功能，但其在裂解周期的任何阶段对识别的影响相对较小。我们的研究结果有助于解释以前发现的抗EBV CD 8 + T细胞反应的免疫优势模式。
CD8+ T cell responses to Epstein-Barr virus (EBV) lytic cycle expressed antigens display a hierarchy of immunodominance, in which responses to epitopes of immediate-early (IE) and some early (E) antigens are more frequently observed than responses to epitopes of late (L) expressed antigens. It has been proposed that this hierarchy, which correlates with the phase-specific efficiency of antigen presentation, may be due to the influence of viral immune-evasion genes. At least three EBV-encoded genes, BNLF2a, BGLF5 and BILF1, have the potential to inhibit processing and presentation of CD8+ T cell epitopes. Here we examined the relative contribution of these genes to modulation of CD8+ T cell recognition of EBV lytic antigens expressed at different phases of the replication cycle in EBV-transformed B-cells (LCLs) which spontaneously reactivate lytic cycle. Selective shRNA-mediated knockdown of BNLF2a expression led to more efficient recognition of immediate-early (IE)- and early (E)-derived epitopes by CD8+ T cells, while knock down of BILF1 increased recognition of epitopes from E and late (L)-expressed antigens. Contrary to what might have been predicted from previous ectopic expression studies in EBV-negative model cell lines, the shRNA-mediated inhibition of BGLF5 expression in LCLs showed only modest, if any, increase in recognition of epitopes expressed in any phase of lytic cycle. These data indicate that whilst BNLF2a interferes with antigen presentation with diminishing efficiency as lytic cycle progresses (IE>E>>L), interference by BILF1 increases with progression through lytic cycle (IE<E<<L). Moreover, double-knockdown experiments showed that BILF1 and BNLF2a co-operate to further inhibit antigen presentation of L epitopes. Together, these data firstly indicate which potential immune-evasion functions are actually relevant in the context of lytic virus replication, and secondly identify lytic-cycle phase-specific effects that provide mechanistic insight into the immunodominance pattern seen for CD8+ T cell responses to EBV lytic antigens. Epstein Barr Virus (EBV), an oncogenic herpesvirus, infects and persists asymptomatically in the majority of humans. In immunocompetent individuals, EBV co-exists with its host as a lifelong infection in the face of strong anti-viral CD8+ T-cell responses. Evasion of this immune-response is presumed to be due in part to immune-modulating mechanisms of certain EBV-encoded proteins expressed during lytic cycle replication. Three such proteins (BNLF2a, BGLF5 and BILF1) have been identified biochemically as able to interfere with HLA-class I antigen presentation. In this study we investigated these proteins in the context of EBV-infected cells in lytic cycle, and their functional recognition by EBV virus-specific CD8+ T-cells. A novel feature of EBV biology was revealed; rather than demonstrating simple redundancy, evasion proteins effect optimum temporal protection at different phases of lytic cycle. BNLF2a strongly inhibited CD8+ T-cell recognition immediately after the EBV-infected cells entered lytic cycle, with its influence waning upon progression to later phases of lytic cycle. Conversely, BILF1 strongly inhibited recognition predominantly at the late phase of lytic cycle. Unexpectedly, despite its well-characterised molecular functions, BGLF5 had relatively little effect on recognition at any stage of lytic cycle. Our results help to explain the previously-identified unusual pattern of immunodominance of anti-EBV CD8+ T-cell responses.
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影响因子：
6.7
作者：
Croft NP;Smith SA;Wong YC;Tan CT;Dudek NL;Flesch IE;Lin LC;Tscharke DC;Purcell AW
通讯作者：
Purcell AW
影响因子：
4.4
作者：
Busche, Andreas;Jirmo, Adan Chari;Messerle, Martin
通讯作者：
Messerle, Martin
DOI：
10.4049/jimmunol.1301629
发表时间：
2013-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Abbott RJ;Quinn LL;Leese AM;Scholes HM;Pachnio A;Rickinson AB
通讯作者：
Rickinson AB
影响因子：
29.7
作者：
Blum JS;Wearsch PA;Cresswell P
通讯作者：
Cresswell P
影响因子：
6.7
作者：
Croft NP;Shannon-Lowe C;Bell AI;Horst D;Kremmer E;Ressing ME;Wiertz EJ;Middeldorp JM;Rowe M;Rickinson AB;Hislop AD
通讯作者：
Hislop AD