T cells play a crucial role in viral clearance and vaccine responses; however, the mechanisms that regulate their homeostasis during viral infections remain unclear. In this study, we investigated the machineries of T-cell homeostasis and telomeric DNA damage using a human model of hepatitis C virus (HCV) infection. We found that naïve CD4 T cells in chronically HCV-infected patients (HCV T cells) were significantly reduced due to apoptosis compared with age-matched healthy subjects (HSs). These HCV T cells were not only senescent, as demonstrated by overexpression of aging markers and particularly shortened telomeres; but also DNA damaged, as evidenced by increased dysfunctional telomere-induced foci (TIF). Mechanistically, the telomere shelterin protein, in particular telomeric repeat binding factor 2 (TRF2) that functions to protect telomeres from DNA damage, was significantly inhibited posttranscriptionally via the p53-dependent Siah-1a ubiquitination. Importantly, knockdown of TRF2 in healthy T cells resulted in increases in telomeric DNA damage and T-cell apoptosis, whereas overexpression of TRF2 in HCV T cells alleviated telomeric DNA damage and T-cell apoptosis. To the best of our knowledge, this is the first report revealing that inhibition of TRF2 promotes T-cell telomere attrition and telomeric DNA damage that accelerates T-cell senescent and apoptotic programs, which contribute to naïve T-cell loss during viral infection. Thus, restoring the impaired T-cell telomeric shelterin machinery may offer a new strategy to improve immunotherapy and vaccine response against human viral diseases.
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Nguyen, Lam Nhat; Zhao, Juan; Cao, Dechao; Dang, Xindi; Wang, Ling; Lian, Jianqi; Zhang, Ying; Jia, Zhansheng; Wu, Xiao Y.; Morrison, Zheng; Xie, Qian; Ji, Yingjie; Zhang, Zheng; El Gazzar, Mohammed; Ning, Shunbin; Moorman, Jonathan P.; and Yao, Zhi Q.. 2018. Inhibition of TRF2 Accelerates Telomere Attrition and DNA Damage in Naïve CD4 T Cells During HCV Infection. Cell Death and Disease. Vol.9(9). 1-13. https://doi.org/10.1038/s41419-018-0897-y ISSN: 2625-2899