Adenosine deaminase modulation of telomerase activity and replicative senescence in human CD8 T lymphocytes.
Adenosine deaminase modulation of telomerase activity and replicative senescence in human CD8 T lymphocytes.
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DOI：
10.4049/jimmunol.0903647
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发表时间：
2010-03-15
期刊：
影响因子：
--
通讯作者：
Effros RB
中科院分区：
文献类型：
--
作者：
Parish ST;Kim S;Sekhon RK;Wu JE;Kawakatsu Y;Effros RB
据记录，在衰老和慢性感染 HIV-1 期间，缺乏 CD28 共刺激受体表达的 CD8 T 淋巴细胞比例增加，并且它们的丰度与许多有害的临床结果相关。经过多轮 Ag 驱动的增殖后，CD28 阴性细胞也会出现在 CD8+CD28+ 细胞培养物中，达到复制衰老的末期。本研究探讨了第二种 T 细胞共刺激受体成分腺苷脱氨酶 (ADA) 在复制衰老过程中的作用。我们之前曾报道过 CD28 信号传导是最佳端粒酶上调所必需的。在这项研究中，我们发现 ADA+ 的 CD8+CD28+ T 淋巴细胞比那些不表达 ADA 的细胞具有显着更高的端粒酶活性，并且随着培养物的衰老，ADA 逐渐丧失。由于 ADA 将腺苷转化为肌苷，缺乏这种酶的细胞可能会长期暴露于腺苷，从而产生免疫抑制作用。事实上，我们发现 CD8 T 淋巴细胞长期暴露于外源腺苷会加速复制衰老过程，导致整体增殖潜力降低、端粒酶活性降低和 IL-2 基因转录减弱。 CD28 表达的丧失加速，部分原因是腺苷诱导组成型 caspase-3 的增加，已知该 caspase-3 作用于 CD28 启动子。这些发现为 ADA 在调节复制衰老过程中的作用提供了第一个证据，并表明增强这种酶的策略可能会为与衰老 CD8 T 淋巴细胞增加相关的病理学带来新的治疗方法。
Increased proportions of CD8 T lymphocytes lacking expression of the CD28 costimulatory receptor have been documented during both aging and chronic infection with HIV-1, and their abundance correlates with numerous deleterious clinical outcomes. CD28-negative cells also arise in cell cultures of CD8+CD28+ following multiple rounds of Ag-driven proliferation, reaching the end stage of replicative senescence. The present study investigates the role of a second T cell costimulatory receptor component, adenosine deaminase (ADA), on the process of replicative senescence. We had previously reported that CD28 signaling is required for optimal telomerase upregulation. In this study, we show that the CD8+CD28+ T lymphocytes that are ADA+ have significantly greater telomerase activity than those that do not express ADA and that ADA is progressively lost as cultures progress to senescence. Because ADA converts adenosine to inosine, cells lacking this enzyme might be subject to prolonged exposure to adenosine, which has immunosuppressive effects. Indeed, we show that chronic exposure of CD8 T lymphocytes to exogenous adenosine accelerates the process of replicative senescence, causing a reduction in overall proliferative potential, reduced telomerase activity, and blunted IL-2 gene transcription. The loss of CD28 expression was accelerated, in part due to adenosine-induced increases in constitutive caspase-3, known to act on the CD28 promoter. These findings provide the first evidence for a role of ADA in modulating the process of replicative senescence and suggest that strategies to enhance this enzyme may lead to novel therapeutic approaches for pathologies associated with increases in senescent CD8 T lymphocytes.
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DOI：
10.1016/j.bbrc.2008.07.059
发表时间：
2008-10-24
影响因子：
3.1
作者：
Hilaire, Cynthia St.;Koupenova, Milka;Carroll, Shannon H.;Smith, Barbara D.;Ravid, Katya
通讯作者：
Ravid, Katya
影响因子：
3.9
作者：
Appay, Victor;Almeida, Jorge R.;Papagno, Laura
通讯作者：
Papagno, Laura
影响因子：
3.8
作者：
Lewis, DE;Yang, LX;Rodgers, JR
通讯作者：
Rodgers, JR
影响因子：
4.3
作者：
DOSREIS, GA;NOBREGA, AF;DECARVALHO, RP
通讯作者：
DECARVALHO, RP
影响因子：
3.2
作者：
ARAN, JM;COLOMER, D;FRANCO, R
通讯作者：
FRANCO, R