Discovering naturally processed antigenic determinants that confer protective T cell immunity
Discovering naturally processed antigenic determinants that confer protective T cell immunity
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DOI：
10.1172/jci67388
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发表时间：
2013-05-01
影响因子：
15.9
通讯作者：
Joyce, Sebastian
中科院分区：
文献类型：
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作者：
Gilchuk, Pavlo;Spencer, Charles T.;Joyce, Sebastian
CD8(+) T细胞（TCD8）赋予对许多传染病的保护性免疫，表明微生物TCD8决定因子是有希望的疫苗靶点。然而，目前的T细胞抗原鉴定方法并不能辨别哪些表位在活动性感染期间驱动保护性免疫，而这些信息对于合理设计tcd8靶向疫苗至关重要。我们采用基于蛋白质组学的方法大规模发现了源自复杂病原体牛痘病毒（VACV）的自然处理决定因子，该决定因子由四种主要HLA I类超型的最常见代表呈现。免疫特性显示，许多以前未识别的VACV决定因子被接种天花的人外周血细胞以一种多样化的方式识别。许多这样的决定因素也被HLA - i类转基因小鼠免疫TCD8识别，并引发保护性TCD8免疫对抗致命的鼻内疫苗感染。值得注意的是，免疫决定因子的有效处理和稳定呈递以及TCD8初始前体的可用性足以驱动多功能、保护性的TCD8反应。我们的方法利用对T细胞表位加工和呈现的基本见解来确定具有复杂蛋白质组的人类病原体中保护性TCD8免疫的靶标，这表明该方法在疫苗科学中具有普遍适用性。
CD8(+) T cells (TCD8) confer protective immunity against many infectious diseases, suggesting that microbial TCD8 determinants are promising vaccine targets. Nevertheless, current T cell antigen identification approaches do not discern which epitopes drive protective immunity during active infection information that is critical for the rational design of TCD8-targeted vaccines. We employed a proteomics-based approach for large-scale discovery of naturally processed determinants derived from a complex pathogen, vaccinia virus (VACV), that are presented by the most frequent representatives of four major HLA class I supertypes. Immunologic characterization revealed that many previously unidentified VACV determinants were recognized by smallpox-vaccinated human peripheral blood cells in a variegated manner. Many such determinants were recognized by HLA class I-transgenic mouse immune TCD8 too and elicited protective TCD8 immunity against lethal intranasal VACV infection. Notably, efficient processing and stable presentation of immune determinants as well as the availability of naive TCD8 precursors were sufficient to drive a multifunctional, protective TCD8 response. Our approach uses fundamental insights into T cell epitope processing and presentation to define targets of protective TCD8 immunity within human pathogens that have complex proteomes, suggesting that this approach has general applicability in vaccine sciences.