Telomerase induction in T cells: A cure for aging and disease?
Telomerase induction in T cells: A cure for aging and disease?
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DOI：
10.1016/j.exger.2006.11.005
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发表时间：
2007-05-01
影响因子：
3.9
通讯作者：
Effros, Rita B.
中科院分区：
文献类型：
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作者：
Effros, Rita B.
免疫系统的细胞在正常体细胞中是独一无二的，因为它们有能力上调端粒延伸酶，端粒酶，尽管是以一种精确控制的方式。长期T细胞培养中端粒酶活性的动力学分析表明，高水平的端粒酶诱导与激活在3-5天达到峰值，然后在3周内下降。这个过程在二次抗原刺激过程中重演，但在体外第三次和所有后续刺激中，CD8 T细胞无法上调端粒酶。缺乏端粒酶活性的细胞分裂导致端粒逐渐缩短，最终，DNA损伤/细胞周期停滞，这是端粒极短的信号。衰老CD8 T细胞的培养显示细胞因子模式改变，抗凋亡，缺乏CD28共刺激受体的表达。在HIV-1慢性感染期间，具有这些和其他复制性衰老特征的CD8 T细胞随着年龄的增长而逐渐积累，并以加速的速度积累。临床研究表明，具有衰老表型的CD8 T细胞的高比例与几种有害的生理结果相关，包括疫苗反应差、骨质流失和促炎细胞因子增加。CD8(+)CD28(-) T细胞也显示出对其他免疫细胞的抑制活性。基于端粒缩短在复制性衰老程序中的核心作用，我们正在开发几种基于端粒酶的方法作为潜在的免疫增强治疗衰老和HIV疾病。用端粒酶催化成分（hTERT）对hiv特异性CD8 T细胞进行基因治疗，可增强增殖能力，增强抗病毒功能，延缓CD28表达的丧失，而核型或生长动力学没有变化。这些原理证明研究已经导致筛选可能模仿基因治疗效果的药理学方法，以更适合临床的配方。(C) 2006爱思唯尔公司版权所有。
Cells of the immune system are unique among normal somatic cells in that they have the capacity to upregulate the telomere-extending enzyme, telomerase, albeit in a precisely controlled fashion. Kinetic analysis of telomerase activity in long-term T cell cultures has documented that the high level of telomerase induced in concert with activation reaches a peak at 3-5 days, then declines by 3 weeks. The process is recapitulated during secondary antigenic stimulation, but by the third, and all subsequent stimulations in vitro, CD8 T cells are unable to upregulate telomerase. Cell division in the absence of telomerase activity results in progressive telomere shortening, and ultimately, the DNA damage/cell cycle arrest that is signaled by critically short telomeres. Cultures of senescent CD8 T cells show altered cytokine patterns, resistance to apoptosis, and absence of expression of the CD28 costimulatory receptor. CD8 T cells with these and other features of replicative senescence accumulate progressively with age, and at an accelerated rate, during chronic infection with HIV-1. Clinical studies have shown that high proportions of CD8 T cells with the senescent phenotype correlate with several deleterious physiologic outcomes, including poor vaccine responses, bone loss, and increased proinflammatory cytokines. CD8(+)CD28(-) T cells have also been shown to exert suppressive activity on other immune cells. Based on the central role of telomere shortening in the replicative senescence program, we are developing several telomerase-based approaches as potential immunoenhancing treatments for aging and HIV disease. Gene therapy of HIV-specific CD8 T cells with the telomerase catalytic component (hTERT) results in enhanced proliferative capacity, increased anti-viral functions, and a delay in the loss of CD28 expression, with no changes in karyotype or growth kinetics. These proof-of-principle studies have led to screening for pharmacological approaches that might mimic the gene therapy effects, in a more clinically suitable formulation. (C) 2006 Elsevier Inc. All rights reserved.