Broadly reactive human CD8 T cells that recognize an epitope conserved between VZV, HSV and EBV.
Broadly reactive human CD8 T cells that recognize an epitope conserved between VZV, HSV and EBV.
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识别VZV，HSV和EBV之间保守的表位的广泛反应性人CD8 T细胞。
DOI：
10.1371/journal.ppat.1004008
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发表时间：
2014-03
期刊：
影响因子：
6.7
通讯作者：
Ahmed R
中科院分区：
文献类型：
--
作者：
Chiu C;McCausland M;Sidney J;Duh FM;Rouphael N;Mehta A;Mulligan M;Carrington M;Wieland A;Sullivan NL;Weinberg A;Levin MJ;Pulendran B;Peters B;Sette A;Ahmed R
人疱疹病毒是潜在严重慢性感染的重要病因，据信T细胞对控制这些感染是必需的。为了研究病毒特异性CD8 T细胞在对抗水痘 - 带状疱疹病毒（VZV）中的作用，我们通过计算机预测生成了一组全面的潜在表位，并在VZV血清阳性的健康供体中筛选T细胞反应。我们在VZV核糖核苷酸还原酶亚基2中鉴定出一个主要的受HLA - A*0201限制的表位，并使用四聚体分析该表位特异性CD8 T细胞的表型和功能。有趣的是，对该VZV表位有反应的CD8 T细胞不仅能识别其他α - 疱疹病毒（单纯疱疹病毒1型和2型）中的同源表位，还能识别γ - 疱疹病毒（EB病毒）中的同源表位。针对这些表位的反应不依赖于先前对源病毒的感染，这表明该T细胞群体具有交叉反应性。在个体之间，这些细胞表现出显著的表型异质性。这与功能能力的差异有关，这种差异与抑制性受体表达增加（包括PD - 1）以及共刺激分子表达减少有关，这可能反映了它们的刺激史。接种减毒活疫苗Zostavax并不能有效刺激该表位特异性群体的增殖反应。因此，我们鉴定出一个在四种临床上重要的疱疹病毒中保守的人CD8 T细胞表位，但当前的成人VZV疫苗对其增强作用不佳。我们讨论了这一发现所引发的“泛疱疹病毒”疫苗的概念以及为实现这一目标可能需要克服的障碍。
人疱疹病毒可引起多种严重感染。它们极为常见，个体终身处于潜伏感染状态，病毒的再激活常常导致复发或严重疾病。T细胞在控制疱疹病毒感染和防止其再激活方面非常重要，因此诱导T细胞的疫苗可能会改善对感染的控制。在此，我们研究了针对VZV的人T细胞，这可能有助于有针对性地开发疫苗。我们确定了一个主要的靶点，大多数受试者针对该靶点产生了CD8 T细胞反应。我们发现非常相似的靶点也存在于其他三种重要的疱疹病毒（单纯疱疹病毒1型、2型和EB病毒）中。我们表明识别VZV靶点的CD8 T细胞也能识别其他病毒的靶点，我们假设与这些病毒的反复接触可能会增强这种共同反应。在一些个体中，接种VZV疫苗确实会引起这些细胞的激活，但在大多数个体中则不会。这反映了当前可用的VZV疫苗效果不一。我们的研究结果表明，T细胞靶点可能在疱疹病毒种类之间共享，因此可能有助于开发一种新型的“泛疱疹病毒”疫苗。然而，当前的VZV疫苗无法可靠地刺激这些T细胞，需要新的策略来实现这一目标。
Human herpesviruses are important causes of potentially severe chronic infections for which T cells are believed to be necessary for control. In order to examine the role of virus-specific CD8 T cells against Varicella Zoster Virus (VZV), we generated a comprehensive panel of potential epitopes predicted in silico and screened for T cell responses in healthy VZV seropositive donors. We identified a dominant HLA-A*0201-restricted epitope in the VZV ribonucleotide reductase subunit 2 and used a tetramer to analyze the phenotype and function of epitope-specific CD8 T cells. Interestingly, CD8 T cells responding to this VZV epitope also recognized homologous epitopes, not only in the other α-herpesviruses, HSV-1 and HSV-2, but also the γ-herpesvirus, EBV. Responses against these epitopes did not depend on previous infection with the originating virus, thus indicating the cross-reactive nature of this T cell population. Between individuals, the cells demonstrated marked phenotypic heterogeneity. This was associated with differences in functional capacity related to increased inhibitory receptor expression (including PD-1) along with decreased expression of co-stimulatory molecules that potentially reflected their stimulation history. Vaccination with the live attenuated Zostavax vaccine did not efficiently stimulate a proliferative response in this epitope-specific population. Thus, we identified a human CD8 T cell epitope that is conserved in four clinically important herpesviruses but that was poorly boosted by the current adult VZV vaccine. We discuss the concept of a “pan-herpesvirus” vaccine that this discovery raises and the hurdles that may need to be overcome in order to achieve this. Human herpesviruses can cause a wide range of serious infections. They are extremely common and individuals remain latently infected lifelong, with reactivations often causing recurrent or severe disease. T-cells are important in controlling herpesvirus infections and preventing their reactivation, so vaccines that induce T-cells are likely to improve control. Here, we examined human T-cells against VZV that might allow focused vaccine development. We identified a dominant target against which the majority of subjects had mounted a CD8 T-cell response. We found that very similar targets also exist in three other important herpesviruses, HSV-1, HSV-2 and EBV. We showed that CD8 T-cells recognizing the VZV target could also recognize the others and we hypothesized that recurrent encounter with these viruses could boost this common response. In some individuals, immunization with a VZV vaccine did cause activation of these cells, but in most it did not. This reflects the variable efficacy of the currently available VZV vaccine. Our findings suggest that T-cell targets may be shared between herpesvirus species and may therefore contribute to a novel “pan-herpesvirus” vaccine. However, current VZV vaccines cannot reliably stimulate these T-cells and new strategies will be necessary to achieve this goal.
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影响因子：
--
作者：
Abendroth, Allison;Kinchington, Paul R.;Slobedman, Barry
通讯作者：
Slobedman, Barry
影响因子：
4.4
作者：
Masopust, David;Ha, Sang-Jun;Ahmed, Rafi
通讯作者：
Ahmed, Rafi
影响因子：
5.4
作者：
HEINEMAN, TC;COHEN, JI
通讯作者：
COHEN, JI
影响因子：
5.5
作者：
Patterson-Bartlett, Julie;Levin, Myron J.;Weinberg, Adriana
通讯作者：
Weinberg, Adriana
DOI：
10.1084/jem.20070256
发表时间：
2007-08-06
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hislop AD;Ressing ME;van Leeuwen D;Pudney VA;Horst D;Koppers-Lalic D;Croft NP;Neefjes JJ;Rickinson AB;Wiertz EJ
通讯作者：
Wiertz EJ