Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
J Immunol. 2010 Mar 15;184(6):2847-54. doi: 10.4049/jimmunol.0903647. Epub 2010 Feb 10.
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.
在衰老和慢性感染 HIV-1 的过程中，已经记录到缺乏 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。在多次抗原驱动的增殖后，CD8(+)CD28(+)细胞培养物中也会出现 CD28 阴性细胞，并达到复制性衰老的终末阶段。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) 在复制性衰老过程中的作用。我们之前曾报道过 CD28 信号对于最佳端粒酶上调是必需的。在这项研究中，我们表明 CD28(+)的 CD8(+)T 淋巴细胞 ADA(+)具有显著更高的端粒酶活性，而那些不表达 ADA 的细胞则没有，并且随着培养物进展到衰老，ADA 逐渐丢失。因为 ADA 将腺苷转化为肌苷，所以缺乏这种酶的细胞可能会长时间暴露于具有免疫抑制作用的腺苷中。事实上，我们表明慢性暴露于外源性腺苷会加速 CD8 T 淋巴细胞的复制性衰老过程，导致整体增殖潜力降低、端粒酶活性降低以及 IL-2 基因转录减弱。CD28 表达的丧失加速了，部分原因是由于腺苷诱导的组成型 caspase-3 增加，已知该酶作用于 CD28 启动子。这些发现为 ADA 在调节复制性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为与衰老 CD8 T 淋巴细胞增加相关的病理学提供新的治疗方法。
