Role of CD8 T Cell Replicative Senescence in Human Aging and in HIV-mediated Immunosenescence.
Role of CD8 T Cell Replicative Senescence in Human Aging and in HIV-mediated Immunosenescence.
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发表时间：
2011-05
影响因子：
7.4
通讯作者：
Jeffrey Dock;R. Effros
中科院分区：
文献类型：
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作者：
Jeffrey Dock;R. Effros
随着人类年龄的增长，他们的免疫系统经历了一个称为免疫衰老的过程。免疫系统的这种全面老化与感染性疾病和癌症的易感性增加、疫苗接种有效性降低、自身免疫现象增加以及由于炎症失调引起的组织损伤有关。免疫衰老的一个标志性特征是具有复制性衰老特征的晚期分化的记忆性CD8 T细胞的积累，所述复制性衰老特征例如不能增殖、缺乏CD28表达、端粒缩短、端粒酶活性丧失和炎性细胞因子分泌增强。衰老的CD8 T细胞的比例随着年龄的增长而逐渐增加，并且通常由对巨细胞病毒（CMV）抗原特异性的寡克隆群体组成。此外，有证据表明，衰老记忆CD8 T细胞获得抑制功能，也可能有助于致癌作用。慢性HIV疾病，即使通过抗逆转录病毒治疗（ART）得到控制，也与加速的免疫衰老有关，正如衰老记忆CD8 T细胞数量增加和炎症环境增加所证明的那样。有趣的是，即使在HIV疾病中，高比例的晚期分化的、脓毒衰老的、记忆性CD8 T细胞对CMV抗原具有特异性。与年龄相关的免疫衰老一样，这些HIV相关的变化导致免疫失调、与炎性损伤相关的慢性疾病以及发病率和死亡率增加。本文综述了CD8 T细胞复制性衰老在体外和体内的证据，在时间老化和艾滋病毒介导的免疫衰老的背景下。我们还强调了我们对人类免疫衰老的理解中的一个重要差距，因为迄今为止所有的研究都集中在外周血中，其中包含全身淋巴细胞群的少数。
As humans age, their immune systems undergo a process known as immunosenescence. This global aging of the immune system is associated with increased susceptibility to infectious diseases and cancer, reduced effectiveness of vaccination, increased autoimmune phenomena, and tissue damage due to dysregulated inflammation. One hallmark feature of immunosenescence is the accumulation of late-differentiated memory CD8 T cells with features of replicative senescence, such as inability to proliferate, absence of CD28 expression, shortened telomeres, loss of telomerase activity, and enhanced secretion of inflammatory cytokines. The proportion of senescent CD8 T cells increases progressively with age, and often consists of oligoclonal populations that are specific for cytomegalovirus (CMV) antigens. In addition, there is evidence that senescent memory CD8 T cells acquire suppressive functions and may also contribute to carcinogenesis. Chronic HIV disease, even when controlled through antiretroviral therapy (ART), is associated with accelerated immunosenescence, as evidenced by the higher numbers of senescent memory CD8 T cells and increased inflammatory milieu. Interestingly, even in HIV disease, a high proportion of late-differentiated, putatively senescent, memory CD8 T cells are specific for CMV antigens. As in age-related immunosenescence, these HIV-associated changes result in dysregulated immunity, chronic diseases linked to inflammatory damage, and increased morbidity and mortality. This review explores the evidence for CD8 T cell replicative senescence in vitro and in vivo, in the context of both chronological aging and HIV-mediated immunosenescence. We also highlight an important gap in our understanding of human immunosenescence, since all the studies to date have focused on peripheral blood, which contains a minority of the total body lymphocyte population.