Defective T Memory Cell Differentiation after Varicella Zoster Vaccination in Older Individuals.
Defective T Memory Cell Differentiation after Varicella Zoster Vaccination in Older Individuals.
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老年人接种水痘带状疱疹疫苗后T记忆细胞分化缺陷。
DOI：
10.1371/journal.ppat.1005892
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发表时间：
2016-10
期刊：
影响因子：
6.7
通讯作者：
Goronzy JJ
中科院分区：
文献类型：
--
作者：
Qi Q;Cavanagh MM;Le Saux S;Wagar LE;Mackey S;Hu J;Maecker H;Swan GE;Davis MM;Dekker CL;Tian L;Weyand CM;Goronzy JJ
接种减毒活水痘带状疱疹病毒(VZV)可以防止带状疱疹重新激活，但保护是不完整的，特别是在老年人口中。为了破译不同疫苗反应背后的分子机制，对不同年龄的人，包括同卵双胞胎，检测了T细胞和B细胞对VZV疫苗的反应。与VZV特异性抗体的诱导相反，抗原特异性T细胞反应受到遗传因素的显著影响。老年人长寿记忆T细胞的生成减少主要是由于高峰应答后T细胞丢失增加所致，而抗原特异性T细胞的扩增不受年龄的影响。激活的CD4T细胞在峰值反应时的基因表达确定了与细胞周期调节和DNA修复相关的基因模块，这些基因模块与T细胞反应的收缩阶段相关，从而产生了长寿命记忆细胞。这些数据确定了细胞周期调节机制作为目标，以减少疫苗反应中的T细胞磨损，并改善抗原特异性T细胞记忆的生成，特别是在老年人群中。疫苗接种是最成功的医疗干预措施之一，但它在老年人口中失去了效力，因为老年人口特别容易感染传染病。由水痘病毒重新激活引起的带状疱疹就是一个很好的例子。几乎每两个人中就有两个人在80岁之前经历过带状疱疹，而带状疱疹疫苗只能起到部分保护作用。改善疫苗反应的尝试大多是经验性的。疫苗接种诱导抗原特异性T细胞的快速扩张，频率在一到两周后达到顶峰。大多数扩增的T细胞在高峰反应后死亡，只有少数T细胞存活下来，以提供免受感染或带状疱疹病毒再激活的保护。大多数疫苗研究都集中在反应的早期阶段，即T细胞是如何激活和扩张的。令人惊讶的是，在我们的带状疱疹疫苗研究中，峰值反应后T细胞的存活是决定记忆T细胞频率的主要因素。T细胞磨损率随着年龄的增长而增加，与遗传易感性无关。利用系统生物学工具，我们发现了几条参与T细胞分裂和DNA修复的途径，可以针对这些途径来提高T细胞的存活率，从而提高疫苗接种的有效性。
Vaccination with attenuated live varicella zoster virus (VZV) can prevent zoster reactivation, but protection is incomplete especially in an older population. To decipher the molecular mechanisms underlying variable vaccine responses, T- and B-cell responses to VZV vaccination were examined in individuals of different ages including identical twin pairs. Contrary to the induction of VZV-specific antibodies, antigen-specific T cell responses were significantly influenced by inherited factors. Diminished generation of long-lived memory T cells in older individuals was mainly caused by increased T cell loss after the peak response while the expansion of antigen-specific T cells was not affected by age. Gene expression in activated CD4 T cells at the time of the peak response identified gene modules related to cell cycle regulation and DNA repair that correlated with the contraction phase of the T cell response and consequently the generation of long-lived memory cells. These data identify cell cycle regulatory mechanisms as targets to reduce T cell attrition in a vaccine response and to improve the generation of antigen-specific T cell memory, in particular in an older population. Vaccination is one of the most successful medical interventions, but it loses its effectiveness in an older population that is of particular risk for infectious diseases. Shingles, caused by the reactivation of the chickenpox virus, is a prime example. Nearly every second individual has experienced shingles by the age of 80 years, and the shingles vaccine is only partially protective. Attempts to improve the vaccine response are mostly empiric. Vaccinations induce a rapid expansion of antigen-specific T cells with frequencies peaking after one to two weeks. Most expanded T cells die after the peak response, and only few T cells survive to provide protection from infection or, as in case of shingles, from reactivation of latent viruses. Most vaccine studies have focused on the early stages of the response; how T cells are activated and expand. Surprisingly, in our study with the shingle vaccine, T cell survival after the peak response was the major factor determining memory T cell frequencies. T cell attrition was increased with age, independent of genetic predisposition. Using systems biology tools we found several pathways involved in T cell division and DNA repair that could be targeted to improve T cell survival and thereby increase the effectiveness of vaccination.
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影响因子：
5.5
作者：
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通讯作者：
Dekker, Cornelia L.
影响因子：
0.9
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64.5
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通讯作者：
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作者：
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通讯作者：
PLATT, R
影响因子：
17.1
作者：
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通讯作者：
Klickstein, Lloyd B.