Proteome-wide analysis of CD8+ T cell responses to EBV reveals differences between primary and persistent infection.
Proteome-wide analysis of CD8+ T cell responses to EBV reveals differences between primary and persistent infection.
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DOI：
10.1371/journal.ppat.1007110
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发表时间：
2018-09
期刊：
影响因子：
6.7
通讯作者：
Zuo J
中科院分区：
文献类型：
--
作者：
Forrest C;Hislop AD;Rickinson AB;Zuo J
人类疱疹病毒是抗原丰富的病原体，在原发性感染中诱导强烈的CD8+T细胞反应，并持续存在终生，通过反复的裂解复制不断挑战T细胞记忆，并可能影响抗原特异性反应的谱。在这里，我们描述了CD8+ T细胞对γ - 1疱疹病毒，爱泼斯坦-巴尔病毒（EBV）反应的第一个溶解性蛋白质组范围分析，以及第一个对任何人类疱疹病毒的原发性和记忆性CD8+ T细胞反应的蛋白质组范围分析。通过体外有丝分裂扩增，直接从感染性单核细胞增多症（IM）患者血液中活化的CD8+ T细胞制备初级效应制剂。对于记忆制剂，长期病毒携带者血液中的ebv特异性细胞首先在体外被装载有被感染细胞裂解物的自体树突状细胞重新刺激，然后像IM细胞一样扩增。每一种类型的7个供体的制剂与供体的HLA I类等位基因结合，对70种EBV裂解周期蛋白进行筛选。在这两种情况下，都检测到针对直接早期（IE）、早期(E)和晚期(L)裂解周期蛋白的多种反应，包括许多迄今为止未被识别的靶标。然而，有趣的是，两个供体组在IE、E和L反应性之间表现出不同的平衡。初级应答优先针对IE和一小群E蛋白，这似乎与它们在感染细胞表面更好地呈现一致，之后表达的病毒逃避完全占据主导地位。相比之下，在病毒载体中，靶选择是平衡的，对关键的IE和E抗原的反应仍然存在，但对L蛋白的选择亚群的反应现在经常突出。我们推断，至少对于EBV来说，长期携带病毒及其低水平的病毒复制和裂解抗原释放与病毒特异性反应的重塑有关。大多数人携带疱疹病毒为终身无症状感染，但在免疫功能低下的个体中可能危及生命。这反映了T细胞，特别是CD8+杀伤T细胞在控制这些药物中的关键作用。可以说，eb病毒是人类疱疹病毒中致病性最强的，初次感染会导致一种严重的流感样疾病，称为传染性单核细胞增多症，持续感染与一系列eb病毒相关的癌症有因果关系。确定哪些病毒蛋白能诱导最强的T细胞反应，对于疫苗设计和ebv相关疾病免疫疗法的开发至关重要。我们报道了CD8+ T细胞对病毒复制（裂解）周期中表达的70种EBV蛋白的全范围反应的首次综合分析。我们发现，在许多人身上，反应往往集中在这70种蛋白质的同一个小子集上；直接早期和特定早期蛋白是原发性感染的主要目标，但随着病毒的持续存在，选择范围扩大到包括关键的晚期周期抗原。这是ebv诱导的CD8+ T细胞反应的第一张完整图片，也是任何人类疱疹病毒在长期携带过程中慢性病毒复制可以重塑病毒特异性T细胞监测的第一个迹象。
Human herpesviruses are antigenically rich agents that induce strong CD8+T cell responses in primary infection yet persist for life, continually challenging T cell memory through recurrent lytic replication and potentially influencing the spectrum of antigen-specific responses. Here we describe the first lytic proteome-wide analysis of CD8+ T cell responses to a gamma1-herpesvirus, Epstein-Barr virus (EBV), and the first such proteome-wide analysis of primary versus memory CD8+ T cell responses to any human herpesvirus. Primary effector preparations were generated directly from activated CD8+ T cells in the blood of infectious mononucleosis (IM) patients by in vitro mitogenic expansion. For memory preparations, EBV-specific cells in the blood of long-term virus carriers were first re-stimulated in vitro by autologous dendritic cells loaded with a lysate of lytically-infected cells, then expanded as for IM cells. Preparations from 7 donors of each type were screened against each of 70 EBV lytic cycle proteins in combination with the donor’s individual HLA class I alleles. Multiple reactivities against immediate early (IE), early (E) and late (L) lytic cycle proteins, including many hitherto unrecognised targets, were detected in both contexts. Interestingly however, the two donor cohorts showed a different balance between IE, E and L reactivities. Primary responses targeted IE and a small group of E proteins preferentially, seemingly in line with their better presentation on the infected cell surface before later-expressed viral evasins take full hold. By contrast, target choice equilibrates in virus carriage with responses to key IE and E antigens still present but with responses to a select subset of L proteins now often prominent. We infer that, for EBV at least, long-term virus carriage with its low level virus replication and lytic antigen release is associated with a re-shaping of the virus-specific response. Herpesviruses are carried by most people as lifelong asymptomatic infections but become life-threatening in immunocompromised individuals. This reflects the crucial role of T cells, especially CD8+ killer T cells, in controlling these agents. EBV is arguably the most pathogenic of the human herpesviruses, with primary infection producing a severe flu-like illness called infectious mononucleosis, and persistent infection being causally linked to a range of EBV-associated cancers. Identifying which viral proteins induce the strongest T cell responses is seen as crucial both to vaccine design and to the development of immune therapies for EBV-associated diseases. We report the first comprehensive analysis of CD8+ T cell responses to the full range of 70 EBV proteins expressed in the virus-replicative (lytic) cycle. We find that, in many people, responses tend to focus on the same small subset of these 70 proteins; the immediate early and particular early proteins are dominant targets in primary infection, but with virus persistence the choice broadens to include key late cycle antigens. This is the first complete picture of EBV-induced CD8+ T cell responses and the first indication for any human herpesvirus that chronic virus replication during long-term carriage can re-shape virus-specific T cell surveillance.
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影响因子：
15.9
作者：
Hislop, AD;Kuo, M;Rickinson, AB
通讯作者：
Rickinson, AB
影响因子：
64.5
作者：
GLUZMAN, Y
通讯作者：
GLUZMAN, Y
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
影响因子：
4.5
作者：
Huang X;Liu J;Dickson RC
通讯作者：
Dickson RC
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