Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly
Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly
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DOI：
10.4049/jimmunol.176.4.2645
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发表时间：
2006-02-15
影响因子：
4.4
通讯作者：
Wikby, A
中科院分区：
文献类型：
--
作者：
Hadrup, SR;Strindhall, J;Wikby, A
与年龄相关的人体免疫系统功能下降被认为对提供抗感染保护的能力具有负面影响，从而导致死亡率增加。在之前的一项对老年人的纵向研究中，我们发现了一种免疫风险表型（IRP），其定义为CD 4/CD 8比值倒置，与死亡率增加和持续CMV感染相关。在这项研究中，我们分析了90岁和中年人的CD 8克隆组成。在90岁以上的老年人中观察到CD 8 T细胞克隆的数量增加，并且与CMV血清阳性相关。令人惊讶的是，与非IRP个体相比，IRP的CMV血清阳性的90岁以上老人的克隆数量显著减少。IRP个体中克隆数的减少与较短的存活时间相关。MHC/肽多聚体染色显示，CMV特异性T细胞的频率在90岁以上高于中年人，但功能完整的细胞的比例显着降低。在IRP个体中发现功能性CMV特异性T细胞的比例最低。一个彻底的纵向分析的CMV特异性T细胞在九十岁显示出一个稳定的模式的频率，表型和克隆组成。我们假设不同的CD 8 T细胞克隆扩增的数量随着个体年龄的增长而增加，可能是作为控制潜伏感染的补偿机制，例如，CMV，但最终达到一个点，其中克隆耗尽导致CD 8克隆库的收缩，与存活率降低相关。
The age-associated decrease in functionality of the human immune system is thought to have a negative impact on the capacity to provide protection against infection, in turn leading to increased incidence of mortality. In a previous longitudinal study of octogenarians, we identified an immune risk phenotype (IRP) in the very elderly defined by an inverted CD4/CD8 ratio, which was associated with increased mortality and persistent CMV infection. In this study, we analyzed the CD8 clonal composition of nonagenarians and middle-aged individuals. An increased number of CD8 T cell clones was observed in the nonagenarians, and was associated with CMV-seropositivity. Surprisingly, CMV-seropositive nonagenarians with the IRP had a significantly lower number of clones compared with non-IRP individuals. The decrease in clone numbers in IRP individuals was associated with shorter survival time. MHC/peptide multimer staining indicated that the frequency of CMV-specific T cells was higher in nonagenarians than in the middle-aged, but the ratio of functionally intact cells was significantly lower. The lowest ratio of functional CMV-specific T cells was found in an IRP individual. A thorough longitudinal analysis of the CMV-specific T cells in nonagenarians showed a stable pattern with respect to frequency, phenotype, and clonal composition. We hypothesize that the number of different CD8 T cell clonal expansions increases as the individual ages, possibly, as a compensatory mechanism to control latent infections, e.g., CMV, but eventually a point is reached where clonal exhaustion leads to shrinkage of the CD8 clonal repertoire, associated with decreased survival.