Kinetics of antigen expression and epitope presentation during virus infection.
Kinetics of antigen expression and epitope presentation during virus infection.
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DOI：
10.1371/journal.ppat.1003129
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发表时间：
2013-01
期刊：
影响因子：
6.7
通讯作者：
Purcell AW
中科院分区：
文献类型：
--
作者：
Croft NP;Smith SA;Wong YC;Tan CT;Dudek NL;Flesch IE;Lin LC;Tscharke DC;Purcell AW
目前关于病毒感染期间抗原呈递给T细胞的动力学的知识非常少，尽管对于我们理解抗病毒免疫具有根本重要性。在这里，我们使用一种先进的质谱方法，同时定量介绍了8个牛痘病毒肽-MHC复合物（表位）感染细胞和它们的来源抗原的数量在感染后的多个时间。结果显示了惊人的1000倍的丰度范围，以及在监测的表位之间惊人的不同动力学。大多数抗原的蛋白质表达开始和表位展示之间的紧密相关性提供了迄今为止最强有力的支持，即抗原呈递在很大程度上与翻译有关，而不是随后的抗原降解。最后，我们显示了这八个表位的表位丰度和免疫优势等级之间的完全断开。这项研究强调了宿主病毒抗原呈递的复杂性，并证明了假设总蛋白水平与表位呈递和免疫原性直接相关的简单模型的弱点。检测病毒感染的主要机制是T细胞识别短肽片段（表位），所述短肽片段（表位）来源于在与I类MHC的复合物中存在于细胞表面的细胞内蛋白质的降解。虽然抗原降解和肽加载到MHC上的机制现在已经很好地理解，但表位呈递的动力学仅针对单个模型抗原进行了研究。我们通过研究牛痘病毒解决了这个问题，最有名的是天花疫苗，使用先进的质谱仪。多个肽-MHC复合物的精确和同时定量显示，从抗病毒T细胞的角度来看，感染细胞的表面提供了令人惊讶的动态景观。此外，病毒蛋白水平的同时测量表明，在大多数情况下，表位的峰呈递发生在最大蛋白积累的同时或之前。最后，我们发现感染细胞上抗原决定簇的丰度与应答T细胞群的大小之间完全脱节。这些数据为T细胞如何观察病毒感染的细胞提供了新的见解，这对我们理解抗病毒免疫和疫苗开发至关重要。
Current knowledge about the dynamics of antigen presentation to T cells during viral infection is very poor despite being of fundamental importance to our understanding of anti-viral immunity. Here we use an advanced mass spectrometry method to simultaneously quantify the presentation of eight vaccinia virus peptide-MHC complexes (epitopes) on infected cells and the amounts of their source antigens at multiple times after infection. The results show a startling 1000-fold range in abundance as well as strikingly different kinetics across the epitopes monitored. The tight correlation between onset of protein expression and epitope display for most antigens provides the strongest support to date that antigen presentation is largely linked to translation and not later degradation of antigens. Finally, we show a complete disconnect between the epitope abundance and immunodominance hierarchy of these eight epitopes. This study highlights the complexity of viral antigen presentation by the host and demonstrates the weakness of simple models that assume total protein levels are directly linked to epitope presentation and immunogenicity. A major mechanism for the detection of virus infection is the recognition by T cells of short peptide fragments (epitopes) derived from the degradation of intracellular proteins presented at the cell surface in a complex with class I MHC. Whilst the mechanics of antigen degradation and the loading of peptides onto MHC are now well understood, the kinetics of epitope presentation have only been studied for individual model antigens. We addressed this issue by studying vaccinia virus, best known as the smallpox vaccine, using advanced mass spectrometry. Precise and simultaneous quantification of multiple peptide-MHC complexes showed that the surface of infected cells provides a surprisingly dynamic landscape from the point of view of anti-viral T cells. Further, concurrent measurement of virus protein levels demonstrated that in most cases, peak presentation of epitopes occurs at the same time or precedes the time of maximum protein build up. Finally, we found a complete disconnect between the abundance of epitopes on infected cells and the size of the responding T cell populations. These data provide new insights into how virus infected cells are seen by T cells, which is crucial to our understanding of anti-viral immunity and development of vaccines.
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影响因子：
9.9
作者：
Caron, Etienne;Vincent, Krystel;Fortier, Marie-Helene;Laverdure, Jean-Philippe;Bramoulle, Alexandre;Hardy, Marie-Pierre;Voisin, Gregory;Roux, Philippe P.;Lemieux, Sebastien;Thibault, Pierre;Perreault, Claude
通讯作者：
Perreault, Claude
影响因子：
8
作者：
Dolan, Brian P.;Bennink, Jack R.;Yewdell, Jonathan W.
通讯作者：
Yewdell, Jonathan W.
DOI：
10.1073/pnas.1112387109
发表时间：
2012-05-01
影响因子：
11.1
作者：
Dolan, Brian P.;Sharma, Aditi A.;Yewdell, Jonathan W.
通讯作者：
Yewdell, Jonathan W.
影响因子：
64.8
作者：
CHICZ, RM;URBAN, RG;STROMINGER, JL
通讯作者：
STROMINGER, JL
影响因子：
20.3
作者：
Granados, Diana Paola;Yahyaoui, Wafaa;Perreault, Claude
通讯作者：
Perreault, Claude