Increased T-bet is associated with senescence of influenza virus-specific CD8 T cells in aged humans
Increased T-bet is associated with senescence of influenza virus-specific CD8 T cells in aged humans
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DOI：
10.1189/jlb.0912438
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发表时间：
2013-06-01
影响因子：
5.5
通讯作者：
Wherry, E. John
中科院分区：
文献类型：
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作者：
Dolfi, Douglas V.;Mansfield, Kathleen D.;Wherry, E. John
老年人在流感和其他病毒感染后的发病率和死亡率增加，尽管以前接触过或接种过疫苗。小鼠和人类的研究表明，随着年龄的增长，流感病毒特异性CD8 T细胞的衰老和/或耗尽增加。然而，衰老和疲劳之间的关系以及导致老年人流感病毒特异性细胞免疫功能下降的潜在转录途径都没有明确的定义。在这里，我们证明了来自老年人的CD8 T细胞表达CD57和KLRG1的百分比增加，以及PD-1和其他抑制性受体，分别是衰老或衰竭的标志。T-box转录因子T-bet和Eome在CD8T细胞中的表达也增加，并与CD57和KLRG1的表达密切相关。来自老年人的流感病毒特异性CD8T细胞功能降低，CD57、KLRG1和T-bet功能相应增加，T-bet是终末分化的分子调节因子。然而，与总的CD8T细胞相比，流感病毒特异性CD8T细胞改变了抑制受体的表达，包括与年轻受试者相比，降低了PD-1。因此，我们的数据表明，在老年受试者中，流感病毒特异性CD8 T细胞的衰老和/或终末分化具有显著的作用。
Aged individuals have increased morbidity and mortality following influenza and other viral infections, despite previous exposure or vaccination. Mouse and human studies suggest increased senescence and/or exhaustion of influenza virus-specific CD8 T cells with advanced age. However, neither the relationship between senescence and exhaustion nor the underlying transcriptional pathways leading to decreased function of influenza virus-specific cellular immunity in elderly humans are well-defined. Here, we demonstrate that increased percentages of CD8 T cells from aged individuals express CD57 and KLRG1, along with PD-1 and other inhibitory receptors, markers of senescence, or exhaustion, respectively. Expression of T-box transcription factors, T-bet and Eomes, were also increased in CD8 T cells from aged subjects and correlated closely with expression of CD57 and KLRG1. Influenza virus-specific CD8 T cells from aged individuals exhibited decreased functionality with corresponding increases in CD57, KLRG1, and T-bet, a molecular regulator of terminal differentiation. However, in contrast to total CD8 T cells, influenza virus-specific CD8 T cells had altered expression of inhibitory receptors, including lower PD-1, in aged compared with young subjects. Thus, our data suggest a prominent role for senescence and/or terminal differentiation for influenza virus-specific CD8 T cells in elderly subjects.