Inhibition of TRF2 accelerates telomere attrition and DNA damage in naïve CD4 T cells during HCV infection

• Published in: Cell death & disease 2018-09, Vol.9 (9), p.900-13, Article 900
• Main Authors: 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, Mohamed, Ning, Shunbin, Moorman, Jonathan P., Yao, Zhi Q.
• Format: Article
• Language: English
• Subjects: 13/2; 14/19; 38; 42; 42/89; 82; Aging; Antibodies; Apoptosis; Apoptosis - physiology; Biochemistry; Biomedical and Life Sciences; CD4 antigen; CD4-Positive T-Lymphocytes - metabolism; CD4-Positive T-Lymphocytes - virology; Cell Biology; Cell Culture; Cells, Cultured; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - physiology; DNA-Binding Proteins - metabolism; HEK293 Cells; Hepacivirus - pathogenicity; Hepatitis C; Hepatitis C - metabolism; Hepatitis C - virology; Homeostasis; Humans; Immunology; Immunotherapy; Infections; Leukocytes, Mononuclear - metabolism; Leukocytes, Mononuclear - virology; Life Sciences; Lymphocytes; Lymphocytes T; p53 Protein; Telomere - metabolism; Telomere-binding protein; Telomeres; Telomeric Repeat Binding Protein 2 - antagonists & inhibitors; TRF2 protein; Tumor Suppressor Proteins - metabolism; Ubiquitination; Vaccines; Viral infections
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-018-0897-y

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.