Specificities of Human CD4+ T Cell Responses to an Inactivated Flavivirus Vaccine and Infection: Correlation with Structure and Epitope Prediction
Specificities of Human CD4+ T Cell Responses to an Inactivated Flavivirus Vaccine and Infection: Correlation with Structure and Epitope Prediction
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DOI：
10.1128/jvi.00196-14
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发表时间：
2014-07-01
影响因子：
5.4
通讯作者：
Heinz, Franz X.
中科院分区：
文献类型：
--
作者：
Schwaiger, Julia;Aberle, Judith H.;Heinz, Franz X.
蜱传脑炎（TBE）病毒在欧洲、中亚和东亚的大部分地区流行，每年造成1万多例人类神经系统疾病病例。它与蚊媒黄热病、登革热、日本脑炎和西尼罗河病毒密切相关，接种全病毒灭活疫苗可有效预防临床疾病。中和抗体直接针对病毒包膜蛋白(E)和公认的免疫相关。然而，CD4(+) T细胞识别病毒结构蛋白中的表位，从而为B细胞产生e特异性抗体提供直接帮助的特异性数据缺乏。因此，我们对接种疫苗的人的CD4(+) T细胞对病毒粒子蛋白的反应进行了研究，并与TBE患者进行了比较。在白细胞介素-2 （IL-2）酶联免疫吸附点（ELISpot）检测中，利用重叠肽获得的数据与衣壳(C)和E蛋白的三维结构以及基于主要组织相容性复合体（MHC） II类肽亲和力的表位预测进行了分析。在C蛋白中，与四个α螺旋中的两个相对应的肽在疫苗者和患者中都占主导地位，而在E蛋白中，免疫优势的一致性仅限于单一结构域（结构域III）的肽。对C的表位预测比对E的要好得多，对跨膜区域的表位预测尤其错误。我们的数据为影响肽加工的蛋白质结构特征的强烈影响提供了证据，导致实验确定的和计算机预测的CD4(+) T细胞表位之间观察到的差异。
Tick-borne encephalitis (TBE) virus is endemic in large parts of Europe and Central and Eastern Asia and causes more than 10,000 annual cases of neurological disease in humans. It is closely related to the mosquito-borne yellow fever, dengue, Japanese encephalitis, and West Nile viruses, and vaccination with an inactivated whole-virus vaccine can effectively prevent clinical disease. Neutralizing antibodies are directed to the viral envelope protein (E) and an accepted correlate of immunity. However, data on the specificities of CD4(+) T cells that recognize epitopes in the viral structural proteins and thus can provide direct help to the B cells producing E-specific antibodies are lacking. We therefore conducted a study on the CD4(+) T cell response against the virion proteins in vaccinated people in comparison to TBE patients. The data obtained with overlapping peptides in interleukin-2 (IL-2) enzyme-linked immunosorbent spot (ELISpot) assays were analyzed in relation to the three-dimensional structures of the capsid (C) and E proteins as well as to epitope predictions based on major histocompatibility complex (MHC) class II peptide affinities. In the C protein, peptides corresponding to two out of four alpha helices dominated the response in both vaccinees and patients, whereas in the E protein concordance of immunodominance was restricted to peptides of a single domain (domain III). Epitope predictions were much better for C than for E and were especially erroneous for the transmembrane regions. Our data provide evidence for a strong impact of protein structural features that influence peptide processing, contributing to the discrepancies observed between experimentally determined and computer-predicted CD4(+) T cell epitopes.