Functional dichotomy of Vδ2 γδ T cells in chronic hepatitis C virus infections: role in cytotoxicity but not for IFN-γ production.

Hepatitis C virus (HCV) causes persistent infection in more than 70% of cases. HCV infection is closely associated with chronic liver inflammation, which may progress to fibrosis, cirrhosis, or hepatocarcinoma. In general, HCV is not directly cytopathic for infected hepatocytes, and liver injury and disease progression are immune mediated1. The host immune response induced by persistent HCV infection contributes not only to viral control but also to liver injury1,2. Chronic HCV infection is characterized by severe immune dysregulation resulting in liver injury and viral persistence3. As to date, the reason why immune system leads to liver injury but can not eradicate HCV is not completely understood. Whereas previous studies have paid much attention to the characteristics and role of CD8 + T cells, CD4 + T cells, and NK cells in chronic HCV infections4,5, relatively little work has been done on the features of γδ T cells in the context of HCV persistence. In humans, γδ T cells represent 1–5% of the circulating T cells in blood, with the majority (50–95%) expressing a Vγ9Vδ2 TCR (hereafter referred as Vδ2 T cells) that serves as an important innate immune component against microbial agents and tumors6,7. Cells in this subset reacts in a major histocompatibility complex (MHC)-unrestricted manner to a set of low m.w. nonpeptide phosphoantigens such as the mevalonate pathway-derived isopentenyl pyrophosphate (IPP) or synthetic phosphoantigen such as bromohydrin pyrophosphate(BrHPP)8,9. Once activated, Vδ2 T cells rapidly secrete high levels of cytokines such as IFN-γ and kill target cells10. Vδ2 T cells have been shown to exert a broad antiviral activity against different viruses such as human immunodeficiency virus (HIV), influenza A (fluA) and could also contribute to the pathology associated with these infections11,12,13. Our group previously reported that Vδ2 T cells were involved in immune response to hepatitis B virus (HBV)14,15,16, another virus that targets liver. Recently, emerging evidence has indicated that Vδ2 T cells might be implicated in HCV infection17,18. Patients with chronic HCV infection show elevated intrahepatic γδ T cells and that γδ T cells have strong cytotoxic activity against hepatocytes, suggesting a pathogenic role for γδ T cells in HCV infection19. Anti-HCV potential of Vδ2 T cells is also expected. In vitro activation of Vδ2 T cells by nonpeptidic antigen inhibits HCV replication and the antiviral activity is mainly mediated by the release of IFN-γ20. Although these studies have partially defined the role of Vδ2 T cells in human HCV infection, the detailed characteristics of Vδ2 T cells during chronic HCV infection need further investigation. In the present study, we analyzed the phenotype and function of Vδ2 T cells in patients with chronic HCV infection. We observed that Vδ2 T cells showed an activated/effector phenotype in HCV-infected patients; in contrast to their upregulated cytolytic enzymes expression and maintenance of degranulation, Vδ2 T cells in patients had a markedly impaired capacity to produce IFN-γ. This polarized phenotype was associated with liver injury and was induced by exposure to IFN-α.