Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
J Clin Immunol. 2010 Nov;30(6):798-805. doi: 10.1007/s10875-010-9449-7. Epub 2010 Aug 19.
CD28 costimulatory signal transduction in T lymphocytes is essential for optimal telomerase activity, stabilization of cytokine mRNAs, and glucose metabolism. During aging and chronic infection with HIV-1, there are increased proportions of CD8 T lymphocytes that lack CD28 expression and show additional features of replicative senescence. Moreover, the abundance of these cells correlates with decreased vaccine responsiveness, early mortality in the very old, and accelerated HIV disease progression. Here, we show that sustained expression of CD28, via gene transduction, retards the process of replicative senescence, as evidenced by enhanced telomerase activity, increased overall proliferative potential, and reduced secretion of pro-inflammatory cytokines. Nevertheless, the transduced cultures eventually do reach senescence, which is associated with increased CTLA-4 gene expression and a loss of CD28 cell surface expression. These findings further elucidate the central role of CD28 in the replicative senescence program, and may ultimately lead to novel therapies for diseases associated with replicative senescence.
CD28 共刺激信号转导在 T 淋巴细胞中对于端粒酶活性、细胞因子 mRNA 的稳定性和葡萄糖代谢至关重要。在衰老和慢性感染 HIV-1 期间，缺乏 CD28 表达并表现出复制性衰老的其他特征的 CD8 T 淋巴细胞比例增加。此外，这些细胞的丰度与疫苗反应性降低、非常老的人早期死亡率增加以及 HIV 疾病进展加速相关。在这里，我们通过基因转导显示 CD28 的持续表达会延迟复制性衰老的过程，这表现为端粒酶活性增强、整体增殖潜力增加和促炎细胞因子分泌减少。然而，转导的培养物最终确实达到衰老，这与 CTLA-4 基因表达增加和 CD28 细胞表面表达丧失有关。这些发现进一步阐明了 CD28 在复制性衰老程序中的核心作用，并可能最终导致与复制性衰老相关疾病的新型治疗方法。
