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首页> 外文期刊>Cell discovery. >Insufficiency of DNA repair enzyme ATM promotes naive CD4 T-cell loss in chronic hepatitis C virus infection
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Insufficiency of DNA repair enzyme ATM promotes naive CD4 T-cell loss in chronic hepatitis C virus infection

机译：DNA修复酶ATM不足会促进慢性丙型肝炎病毒感染时幼稚的CD4 T细胞丢失

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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.
机译：T细胞在病毒清除和疫苗反应中起着至关重要的作用。然而，调节其对病毒感染或疫苗反应的机制仍然难以捉摸。在这项研究中，我们调查了一大批丙型肝炎病毒（HCV）感染者的T细胞稳态，细胞凋亡，DNA损伤和修复机制。我们发现与年龄匹配的健康受试者相比，慢性HCV感染的个体中的幼稚CD4 T细胞（HCV T细胞）明显减少。此外，HCV T细胞易于发生凋亡和DNA损伤，这可以通过增加8-氧鸟嘌呤的表达和由γH2AX/ 53BP1形成的DNA损伤灶来证明-DNA损伤反应的标志。从机制上讲，HCV T细胞中DNA修复酶共济失调毛细血管扩张突变（ATM）的激活受到抑制。在暴露于ATM抑制剂或抑制磷酸肌醇3激酶途径的HCV（核心蛋白）的健康T细胞中，ATM激活也减弱了，从而模拟了HCV T细胞的生物学效应。重要的是，ATM的异位表达足以修复HCV T细胞中的DNA损伤，存活缺陷和细胞功能障碍。我们的结果表明，不足的DNA修复酶ATM导致DNA损伤增加，并使HCV T细胞易于凋亡，从而导致HCV感染中幼稚T细胞的丢失。我们的研究揭示了T细胞失调和病毒持久性的新机制，为改善针对人类病毒性疾病的免疫疗法和疫苗反应提供了新的策略。

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