Hepatocyte-derived exosomes promote T follicular regulatory cell expansion during HCV infection

Abstract

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 the livers of chronic HCV patients that is absent in liver tissues from non-viral hepatitis or healthy subjects. Co-culture of PBMCs from healthy subjects with HCV-infected hepatoma cells resulted in preferential expansion of circulating Tfr cells leading to the suppression of Tfh cells. Additionally, co-culture of tonsillar cells with infected hepatoma cells lead to an expansion of germinal center Tfr. Notably, expansion was mediated by TGF-β-containing exosomes released from HCV-infected hepatocytes as 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. This article is protected by copyright. All rights reserved.

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