T cells protect against hepatitis A virus infection and limit infection-induced liver injury.
T cells protect against hepatitis A virus infection and limit infection-induced liver injury.
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DOI：
10.1016/j.jhep.2021.07.019
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发表时间：
2021-12
影响因子：
25.7
通讯作者：
Whitmire JK
中科院分区：
文献类型：
--
作者：
Misumi I;Mitchell JE;Lund MM;Cullen JM;Lemon SM;Whitmire JK
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，感染导致典型的一过性但偶尔暴发性和致命性炎性肝损伤。病毒特异性T细胞频率在肝损伤处于顶峰时达到峰值，导致普遍认为T细胞会加剧肝脏疾病，正如其他嗜肝病毒感染所怀疑的那样。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。Ifnar 1 −/−小鼠对HAV高度宽容，并发展出重现甲型肝炎许多特征的发病机制。使用该模型，我们通过表位作图鉴定了HAV特异性CD 8+和CD 4 + T细胞，然后使用四聚体和功能测定来定量感染后多个时间点肝脏中的T细胞。我们评估了HAV特异性T细胞频率和病毒RNA量与肝脏发病机制之间的关系。在感染的前1-2周，大量病毒特异性T细胞在Ifnar 1 −/−小鼠的肝脏内积累，并随着时间的推移而持续存在。当小鼠T细胞耗尽时，HAV复制增强，肝脏疾病加重。相反，用肽疫苗免疫增加了肝脏中病毒特异性CD 8 + T细胞的频率，减少了病毒RNA丰度，减轻了肝损伤。这些数据表明，T细胞可以防止HAV介导的肝损伤，并可以靶向改善肝脏健康。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。
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 an historic lack of small animal models. 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 and viral RNA amounts and liver pathogenesis. 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. These data show that T cells protect against HAV-mediated liver injury and can be targeted to improve liver health. 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.
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通讯作者：
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作者：
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