Stage-specific inhibition of MHC class I presentation by the Epstein-Barr virus BNLF2a protein during virus lytic cycle.
Stage-specific inhibition of MHC class I presentation by the Epstein-Barr virus BNLF2a protein during virus lytic cycle.
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DOI：
10.1371/journal.ppat.1000490
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发表时间：
2009-06
期刊：
影响因子：
6.7
通讯作者：
Hislop AD
中科院分区：
文献类型：
--
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
尽管存在强烈的免疫反应，但γ-疱疹病毒Epstein-Barr病毒（EBV）在感染个体中持续存在。在EBV的裂解周期中，许多病毒蛋白质被表达，潜在地允许病毒感染的细胞被CD 8 + T细胞识别和消除。我们最近已经确定了由EBV编码的免疫逃避蛋白，BNLF 2a，其在早期阶段裂解复制中表达并抑制与抗原加工相关的转运蛋白的肽和ATP结合功能。BNLF 2a的异位表达导致表面MHC I类表达降低，并抑制指示抗原向CD 8 + T细胞的呈递。在这里，我们试图研究BNLF 2a在EBV裂解复制过程中自然表达时的影响。我们制备了BNLF 2a缺失的重组EBV（Δ BNLF 2a），并比较了Δ BNLF 2a和野生型EBV转化的B细胞系被EBV编码的立即早期、早期和晚期裂解抗原特异性的CD 8 + T细胞克隆识别的能力。与野生型病毒转化体相比，当由Δ BNLF 2a转化细胞呈递时，来自立即早期和早期表达蛋白的表位被更好地识别。然而，当由野生型和Δ BNLF 2a细胞靶呈递时，CD 8 + T细胞对晚期抗原的识别仍然同样差。BNLF 2a和靶蛋白表达动力学的分析表明，虽然BNLF 2a在早期复制期间表达，但它在立即早期蛋白上调和早期蛋白合成起始时表达。有趣的是，发现BNLF 2a蛋白表达在裂解周期晚期丢失，而Δ BNLF 2a转化的细胞在复制晚期下调表面MHC I类，其程度与野生型EBV转化的细胞相似。这些数据表明，BNLF 2a介导的表达是阶段特异性的，影响即时早期和早期蛋白质的呈递，并且其他逃避机制在裂解周期后期起作用。EB病毒（EBV）由世界上大约90%的人口携带，尽管有强烈的特异性免疫应答，但它仍然存在并长期脱落，其中一个关键组成部分是识别和杀死感染细胞的CD 8 + T细胞。病毒用来逃避这些反应的机制尚不清楚。最近，我们确定了一个由EBV编码的基因，BNLF 2a，当在细胞中异位表达时，会抑制CD 8 + T细胞对其的识别。为了确定BNLF 2a对逃避EBV特异性CD 8 + T细胞识别的贡献以及EBV是否编码额外的免疫逃避机制，构建了BNLF 2a缺失的重组EBV。我们发现，与用非重组病毒感染的细胞相比，用重组病毒感染的细胞更好地被对与BNLF 2a同时表达的靶特异性的CD 8 + T细胞识别。然而，在病毒感染周期的晚期阶段表达的蛋白质被CD 8 + T细胞识别较差，这表明EBV编码额外的免疫逃避基因以防止有效的CD 8 + T细胞识别。这项研究强调了病毒免疫逃避机制的阶段特异性。
The gamma-herpesvirus Epstein-Barr virus (EBV) persists for life in infected individuals despite the presence of a strong immune response. During the lytic cycle of EBV many viral proteins are expressed, potentially allowing virally infected cells to be recognized and eliminated by CD8+ T cells. We have recently identified an immune evasion protein encoded by EBV, BNLF2a, which is expressed in early phase lytic replication and inhibits peptide- and ATP-binding functions of the transporter associated with antigen processing. Ectopic expression of BNLF2a causes decreased surface MHC class I expression and inhibits the presentation of indicator antigens to CD8+ T cells. Here we sought to examine the influence of BNLF2a when expressed naturally during EBV lytic replication. We generated a BNLF2a-deleted recombinant EBV (ΔBNLF2a) and compared the ability of ΔBNLF2a and wild-type EBV-transformed B cell lines to be recognized by CD8+ T cell clones specific for EBV-encoded immediate early, early and late lytic antigens. Epitopes derived from immediate early and early expressed proteins were better recognized when presented by ΔBNLF2a transformed cells compared to wild-type virus transformants. However, recognition of late antigens by CD8+ T cells remained equally poor when presented by both wild-type and ΔBNLF2a cell targets. Analysis of BNLF2a and target protein expression kinetics showed that although BNLF2a is expressed during early phase replication, it is expressed at a time when there is an upregulation of immediate early proteins and initiation of early protein synthesis. Interestingly, BNLF2a protein expression was found to be lost by late lytic cycle yet ΔBNLF2a-transformed cells in late stage replication downregulated surface MHC class I to a similar extent as wild-type EBV-transformed cells. These data show that BNLF2a-mediated expression is stage-specific, affecting presentation of immediate early and early proteins, and that other evasion mechanisms operate later in the lytic cycle. Epstein-Barr virus (EBV) is carried by approximately 90% of the world's population, where it persists and is chronically shed despite a vigorous specific immune response, a key component of which are CD8+ T cells that recognize and kill infected cells. The mechanisms the virus uses to evade these responses are not clear. Recently we identified a gene encoded by EBV, BNLF2a, that when expressed ectopically in cells inhibited their recognition by CD8+ T cells. To determine the contribution of BNLF2a to evasion of EBV-specific CD8+ T cell recognition and whether EBV encoded additional immune evasion mechanisms, a recombinant EBV was constructed in which BNLF2a was deleted. We found that cells infected with the recombinant virus were better recognized by CD8+ T cells specific for targets expressed co-incidently with BNLF2a, compared to cells infected with a non-recombinant virus. However, proteins expressed at late stages of the viral infection cycle were poorly recognised by CD8+ T cells, suggesting EBV encodes additional immune evasion genes to prevent effective CD8+ T cell recognition. This study highlights the stage-specific nature of viral immune evasion mechanisms.
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DOI：
10.1084/jem.185.9.1605
发表时间：
1997-05-05
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Steven NM;Annels NE;Kumar A;Leese AM;Kurilla MG;Rickinson AB
通讯作者：
Rickinson AB
影响因子：
4.4
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影响因子：
3.7
作者：
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PEARSON, GR
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DOI：
10.1084/jem.184.5.1791
发表时间：
1996-11-01
期刊：
The Journal of experimental medicine
影响因子：
--
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DOI：
10.1084/jem.20070256
发表时间：
2007-08-06
期刊：
The Journal of experimental medicine
影响因子：
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作者：
Hislop AD;Ressing ME;van Leeuwen D;Pudney VA;Horst D;Koppers-Lalic D;Croft NP;Neefjes JJ;Rickinson AB;Wiertz EJ
通讯作者：
Wiertz EJ