Insufficiency of DNA repair enzyme ATM promotes naive CD4 T-cell loss in chronic hepatitis C virus infection

• Published in: Cell discovery 2018-04, Vol.4 (1), p.16-13, Article 16
• Main Authors: Zhao, Juan, Dang, Xindi, Zhang, Peixin, Nguyen, Lam Nhat, Cao, Dechao, Wang, Lin, Wu, Xiaoyuan, Morrison, Zheng D, Zhang, Ying, Jia, Zhansheng, Xie, Qian, Wang, Ling, Ning, Shunbin, EL Gazzar, Mohamed, Moorman, Jonathan P, Yao, Zhi Q
• Format: Article
• Language: English
• Subjects: 631/250; 631/80; 8-Hydroxyguanine; Apoptosis; Ataxia telangiectasia mutated protein; Biomedical and Life Sciences; CD4 antigen; Cell activation; Cell Biology; Cell Culture; Cell Cycle Analysis; Cell Physiology; Cell survival; Chronic infection; Core protein; Deoxyribonucleic acid; DNA; DNA damage; DNA repair; Ectopic expression; Enzymes; Hepatitis; Hepatitis C; Homeostasis; Immunization; Immunotherapy; Infections; Kinases; Life Sciences; Lymphocytes; Lymphocytes T; Mimicry; Stem Cells; Vaccines; Viral infections
• ISSN: 2056-5968; 2056-5968
• DOI: 10.1038/s41421-018-0015-4

T cells have a crucial role in viral clearance and vaccine response; however, the mechanisms regulating their responses to viral infections or vaccinations remain elusive. In this study, we investigated T-cell homeostasis, apoptosis, DNA damage, and repair machineries in a large cohort of subjects with hepatitis C virus (HCV) infection. We found that naive CD4 T cells in chronically HCV-infected individuals (HCV T cells) were significantly reduced compared with age-matched healthy subjects. In addition, HCV T cells were prone to apoptosis and DNA damage, as evidenced by increased 8-oxoguanine expression and γH2AX/53BP1-formed DNA damage foci—hallmarks of DNA damage responses. Mechanistically, the activation of DNA repair enzyme ataxia telangiectasia mutated (ATM) was dampened in HCV T cells. ATM activation was also diminished in healthy T cells exposed to ATM inhibitor or to HCV (core protein) that inhibits the phosphoinositide 3 kinase pathway, mimicking the biological effects in HCV T cells. Importantly, ectopic expression of ATM was sufficient to repair the DNA damage, survival deficit, and cell dysfunctions in HCV T cells. Our results demonstrate that insufficient DNA repair enzyme ATM leads to increased DNA damage and renders HCV T cells prone to apoptotic death, which contribute to the loss of naive T cells in HCV infection. Our study reveals a novel mechanism for T-cell dysregulation and viral persistence, providing a new strategy to improve immunotherapy and vaccine responses against human viral diseases.