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

Juan Zhao,Shunbin Ning,Jonathan P Moorman,Peixin Zhang,Ying Zhang,Lin Wang,Xiaoyuan Wu,Dechao Cao,Zhi Q Yao,Zhansheng Jia,Lam Nhat Nguyen,Zheng D Morrison,Xindi Dang,Qian Xie,Mohamed El Gazzar,Ling Wang

doi:10.1038/s41421-018-0015-4

Abstract

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.

Highlights

Introduction HepatitisC virus (HCV) is a blood-born pathogen characterized by a high rate (>80%) of chronic infection, which can progress to liver cirrhosis and hepatocellular carcinoma—a leading cause for liver transplantation[1]
To exclude the possibility that the gated peripheral blood mononuclear cells (PBMCs) may include some CD4-expresing monocytes, we further gated on CD3+ T cells, followed by analyzing CD45RA+CD3+CD4+ and CD45RA−CD3+CD4+ T-cell populations, which produced similar results; i.e., chronic hepatitis C virus (HCV) subjects exhibited a significant contraction of naive T-cell pools and expansion of memory T cells in their peripheral blood
We further demonstrate that homeostatic remodeling of the T-cell repertoire during HCV infection primarily affects the naive T-cell compartment, characterized by an accumulation of DNA damage owing to insufficient activation of the DNA repair ataxia telangiectasia mutated (ATM) enzyme, which leads to naive T-cell apoptosis and loss

Summary

Introduction

Introduction HepatitisC virus (HCV) is a blood-born pathogen characterized by a high rate (>80%) of chronic infection, which can progress to liver cirrhosis and hepatocellular carcinoma—a leading cause for liver transplantation[1]. We hypothesize that premature T-cell aging involves virus-specific effector and memory T cells engaging in chronic viral infection, but may extend to the compartment of naive T cells that are unprimed by antigens In support of this notion, broad regulatory anomalies, including the markers for T-cell exhaustion and senescence, are found expressed on virus-specific T cells, and on unprimed naive T cells that have not yet engaged in immune responses[2,3,4,5,6, 9,10,11,12,13,14]. This notion is supported by the observations that individuals with chronic viral (HCV or HIV) infection often have blunted vaccine responses, suggesting a broad and shared mechanism of immune dysregulation, naive CD4 T-cell dysfunction, and vaccine non-responsiveness in virally infected individuals[2, 3, 15,16,17,18,19]

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Results

Conclusion