Hepatitis C virus (HCV) is a global health concern that can cause severe liver disease, such as cirrhosis and hepatocellular carcinoma. Control of HCV requires vigorous T‐cell responses, yet CD4+ T cells in chronic HCV patients are dysfunctional. T follicular regulatory (Tfr) cells are a subset of regulatory T cells that suppress T follicular helper (Tfh) cells and the generation of high affinity antibody‐producing B cells. In this study, we examined the accumulation of Tfr cells in the liver compartment during chronic HCV infection and defined the cellular and molecular mechanisms underlying their expansion. Our analysis revealed a substantial population of Tfr cells in livers of chronic HCV patients that is absent in liver tissues from nonviral hepatitis or healthy subjects. Coculture of PBMCs from healthy subjects with HCV‐infected hepatoma cells resulted in preferential expansion of circulating Tfr cells, leading to suppression of Tfh cells. Additionally, coculture of tonsillar cells with infected hepatoma cells lead to an expansion of germinal center Tfr. Notably, expansion was mediated by transforming growth factor beta (TGF‐β)‐containing exosomes released from HCV‐infected hepatocytes given that blockade of exosome‐associated TGF‐β or inhibition of exosome release abrogated Tfr expansion. Conclusion: These results show that liver‐derived exosomes play a pivotal role in the accumulation of Tfr cells, likely leading to suppression of Tfh responses in HCV‐infected patients. Our study identifies a novel pathway in which HCV infection in hepatocytes exacerbates Tfr cell responses to subvert antiviral immunity. (Hepatology 2018;67:71‐85)

中文翻译：

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肝细胞来源的外泌体在 HCV 感染期间促进 T 滤泡调节细胞扩增

丙型肝炎病毒 (HCV) 是一种全球性的健康问题，可导致严重的肝脏疾病，例如肝硬化和肝细胞癌。控制 HCV 需要强烈的 T 细胞反应，但慢性 HCV 患者的 CD4+ T 细胞功能失调。T 滤泡调节 (Tfr) 细胞是调节性 T 细胞的一个子集，可抑制 T 滤泡辅助 (Tfh) 细胞和产生高亲和力抗体的 B 细胞的产生。在这项研究中，我们检查了慢性 HCV 感染期间 Tfr 细胞在肝室中的积累，并确定了它们扩增的细胞和分子机制。我们的分析显示，慢性 HCV 患者肝脏中存在大量 Tfr 细胞，非病毒性肝炎或健康受试者的肝组织中不存在这些细胞。来自健康受试者的 PBMC 与感染 HCV 的肝癌细胞共培养导致循环 Tfr 细胞优先扩增，从而抑制 Tfh 细胞。此外，扁桃体细胞与感染的肝癌细胞的共培养导致生发中心 Tfr 的扩张。值得注意的是，由于外泌体相关的 TGF-β 的阻断或外泌体释放的抑制消除了 Tfr 扩增，因此扩增是由 HCV 感染的肝细胞释放的含有转化生长因子 β（TGF-β）的外泌体介导的。结论：这些结果表明，肝脏来源的外泌体在 Tfr 细胞的积累中起关键作用，可能导致 HCV 感染患者的 Tfh 反应受到抑制。我们的研究确定了一种新途径，其中肝细胞中的 HCV 感染会加剧 Tfr 细胞反应以破坏抗病毒免疫。