Early T Cell Recognition of B Cells following Epstein-Barr Virus Infection: Identifying Potential Targets for Prophylactic Vaccination.
Early T Cell Recognition of B Cells following Epstein-Barr Virus Infection: Identifying Potential Targets for Prophylactic Vaccination.
复制标题
DOI：
10.1371/journal.ppat.1005549
复制
发表时间：
2016-04
期刊：
影响因子：
6.7
通讯作者：
Rickinson AB
中科院分区：
文献类型：
--
作者：
Brooks JM;Long HM;Tierney RJ;Shannon-Lowe C;Leese AM;Fitzpatrick M;Taylor GS;Rickinson AB
爱泼斯坦-巴尔病毒是一种b淋巴细胞性疱疹病毒，是传染性单核细胞增多症的病因，与几种恶性肿瘤有很强的病因学联系，并与某些自身免疫性疾病有关。迄今为止，开发预防或减少ebv相关疾病的预防性疫苗的努力主要集中在诱导中和抗体反应上。然而，通过诱导能够识别和杀死最近感染的B细胞的T细胞反应，这种疫苗可能会进一步得到改进。在这种情况下，EBNA2、ena - lp和BHRF1是在B细胞生长转化的初始阶段首先表达的病毒抗原，但作为CD8+ T细胞靶点的特征却很差。在这里，我们描述了CD8+ T细胞对这三种“第一波”蛋白的反应，确定了目标表位和HLA限制等位基因。虽然EBNA-LP和BHRF1各含有一个强CD8表位，但EBNA2中的表位通过几个不太常见的HLA I类等位基因（如B*3801和B*5501）诱导免疫显性反应，以及通过常见的I类等位基因（如B7和C*0304）诱导亚显性反应。重要的是，这种ebna2特异性CD8+ T细胞在感染后的第一天识别B细胞，先于CD8+ T细胞识别特征明确的潜在靶抗原（如EBNA3B或LMP2），并有效抑制ebv转化的B细胞系的生长。我们推断，生长转化感染的“第一波”抗原，特别是EBNA2，构成潜在的CD8+ T细胞免疫原，可纳入预防性EBV疫苗设计。爱泼斯坦-巴尔病毒感染了世界上绝大多数人口；在大多数个体中，初次感染和长期病毒携带者都是无症状的。然而，EBV是腺热的主要原因，与多种癌症有关，并与各种自身免疫性疾病有关；因此，开发一种预防性疫苗的动力很强。迄今为止，疫苗设计主要集中在诱导病毒粒子结构成分的中和抗体，以防止病毒结合和感染。这种策略可以通过包含免疫原来诱导T细胞反应，从而有可能迅速识别和消除被感染的细胞，从而得到改进。在这里，我们描述了T细胞对EBNA2、EBNA-LP和BHRF1三种蛋白的反应，这三种蛋白构成了eb病毒感染B细胞后新生病毒抗原表达的“第一波”。这些蛋白质中的每一种都是供体的一个子集中强烈的T细胞反应的目标。此外，CD8+ T细胞对这些蛋白中的至少一种EBNA2具有特异性，在感染后非常早的时间点就能有效识别B细胞，比所有其他特异性的CD8+ T细胞都要早，并在体外有效地抑制EBV感染后B细胞系的生长。因此，“第一波抗原”，特别是EBNA2，可能包含在预防性EBV疫苗设计中的合适候选免疫原。
Epstein-Barr virus, a B-lymphotropic herpesvirus, is the cause of infectious mononucleosis, has strong aetiologic links with several malignancies and has been implicated in certain autoimmune diseases. Efforts to develop a prophylactic vaccine to prevent or reduce EBV-associated disease have, to date, focused on the induction of neutralising antibody responses. However, such vaccines might be further improved by inducing T cell responses capable of recognising and killing recently-infected B cells. In that context, EBNA2, EBNA-LP and BHRF1 are the first viral antigens expressed during the initial stage of B cell growth transformation, yet have been poorly characterised as CD8+ T cell targets. Here we describe CD8+ T cell responses against each of these three “first wave” proteins, identifying target epitopes and HLA restricting alleles. While EBNA-LP and BHRF1 each contained one strong CD8 epitope, epitopes within EBNA2 induced immunodominant responses through several less common HLA class I alleles (e.g. B*3801 and B*5501), as well as subdominant responses through common class I alleles (e.g. B7 and C*0304). Importantly, such EBNA2-specific CD8+ T cells recognised B cells within the first day post-infection, prior to CD8+ T cells against well-characterised latent target antigens such as EBNA3B or LMP2, and effectively inhibited outgrowth of EBV-transformed B cell lines. We infer that “first wave” antigens of the growth-transforming infection, especially EBNA2, constitute potential CD8+ T cell immunogens for inclusion in prophylactic EBV vaccine design. Epstein-Barr virus infects the vast majority of the world’s population; in most individuals both primary infection and long-term virus carriage are asymptomatic. However, EBV is the major cause of glandular fever, is associated with multiple cancers and is implicated in various autoimmune conditions; thus there is a strong impetus for the development of a prophylactic vaccine. To date, vaccine design has largely focused on the induction of neutralising antibodies to virion structural components which can prevent virus binding and infection. Such strategies may be improved by the inclusion of immunogens to induce T cell responses with the potential to promptly recognise and eliminate cells that do become infected. Here we characterise T cell responses to three proteins, EBNA2, EBNA-LP and BHRF1 that comprise the “first wave” of de novo viral antigen expression following EBV infection of B cells. Each of these proteins is targeted by strong T cell responses in a subset of donors. Furthermore, CD8+ T cells specific for that at least one of these proteins, EBNA2, efficiently recognise B cells at very early time-points post-infection, before CD8+ T cells of all other specificities tested, and effectively inhibit outgrowth of B cell lines following EBV infection in vitro. Thus “first wave antigens”, particularly EBNA2, may comprise suitable candidate immunogens for inclusion in prophylactic EBV vaccine design.