Background & Aims

Hepatitis A virus (HAV) is a common cause of enterically transmitted viral hepatitis. In non-immune individuals, infection results in typically transient but occasionally fulminant and fatal inflammatory liver injury. Virus-specific T cell frequencies peak when liver damage is at its zenith, leading to the prevalent notion that T cells exacerbate liver disease, as suspected for other hepatotropic virus infections. However, the overall contribution of T cells to the control of HAV and the pathogenesis of hepatitis A is unclear and has been impeded by a historic lack of small animal models.

Methods

Ifnar1^-/- mice are highly permissive for HAV and develop pathogenesis that recapitulates many features of hepatitis A. Using this model, we identified HAV-specific CD8+ and CD4+ T cells by epitope mapping, and then used tetramers and functional assays to quantify T cells in the liver at multiple times after infection. We assessed the relationships between HAV-specific T cell frequency, viral RNA amounts, and liver pathogenesis.

Results

A large population of virus-specific T cells accumulated within the livers of Ifnar1^-/- mice during the first 1-2 weeks of infection and persisted over time. HAV replication was enhanced and liver disease exacerbated when mice were depleted of T cells. Conversely, immunization with a peptide vaccine increased virus-specific CD8+ T cell frequencies in the liver, reduced viral RNA abundance, and lessened liver injury.

Conclusion

These data show that T cells protect against HAV-mediated liver injury and can be targeted to improve liver health.

Lay summary

Hepatitis A virus is a leading cause of acute viral hepatitis worldwide. T cells were thought to contribute to liver injury during acute infection. We now show that virus-specific T cells protect against infection and limit liver injury.

中文翻译：

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T 细胞可预防甲型肝炎病毒感染并限制感染引起的肝损伤

背景与目标

甲型肝炎病毒 (HAV) 是肠道传播的病毒性肝炎的常见原因。在非免疫个体中，感染通常会导致短暂但偶尔爆发性和致命的炎症性肝损伤。当肝损伤达到顶峰时，病毒特异性 T 细胞频率达到峰值，导致普遍认为 T 细胞会加剧肝病，这与其他嗜肝病毒感染有关。然而，T 细胞对控制 HAV 和甲型肝炎发病机制的总体贡献尚不清楚，并且由于历史上缺乏小动物模型而受到阻碍。

方法

Ifnar1 ^-/-小鼠高度允许 HAV 并发展出重现甲型肝炎许多特征的发病机制。使用该模型，我们通过表位作图识别 HAV 特异性 CD8+ 和 CD4+ T 细胞，然后使用四聚体和功能测定来量化 T 细胞感染后多次进入肝脏。我们评估了 HAV 特异性 T 细胞频率、病毒 RNA 量和肝脏发病机制之间的关系。

结果

在感染的最初 1-2 周期间，大量病毒特异性 T 细胞在Ifnar1 ^-/-小鼠的肝脏内积累，并随着时间的推移持续存在。当小鼠的 T 细胞耗尽时，HAV 复制增强，肝脏疾病恶化。相反，肽疫苗免疫增加了肝脏中病毒特异性 CD8+ T 细胞的频率，降低了病毒 RNA 的丰度，并减轻了肝损伤。

结论

这些数据表明，T 细胞可防止 HAV 介导的肝损伤，并可用于改善肝脏健康。

总结

甲型肝炎病毒是全球急性病毒性肝炎的主要原因。T 细胞被认为在急性感染期间会导致肝损伤。我们现在表明，病毒特异性 T 细胞可以防止感染并限制肝损伤。