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.
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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.; and Yao, Zhi Q.. 2018. Insufficiency of DNA Repair Enzyme ATM Promotes Naive CD4 T-cell Loss in Chronic Hepatitis C Virus Infection. Cell Discovery. Vol.16(16). 1-13. https://doi.org/10.1038/s41421-018-0015-4 ISSN: 2056-5968