Intrahepatic Vγ9Vδ2 T-cells from HCV-infected patients show an exhausted phenotype but can inhibit HCV replication

Hepatitis C virus (HCV) persistence results from inefficiencies of both innate and adaptive immune responses to eradicate the infection. A functional impairment of circulating V gamma 9V delta 2 T-cells was described but few data are available on V gamma 9V delta 2 T-cells in the liver that, however, represents the battlefield in the HCV/host interaction. Aim of this work was to compare circulating and intrahepatic V gamma 9V delta 2 T-cells in chronic HCV-infected patients (HCVpos) and in HCV-negative (HCVneg) subjects. Phenotypic and functional analysis was performed by flow cytometry. Anti-HCV activity was analyzed by using an in vitro autologous liver culture system. Independently from HCV infection, the liver was enriched of V gamma 9V delta 2 T-cells expressing an effector/activated phenotype. In contrast, an enrichment of PD-1 expressing V gamma 9V delta 2 T-cells was observed both in the peripheral blood and in the liver of HCVpos patients, probably due to a persistent antigenic stimulation. Moreover, a lower frequency of IFN-gamma producing V gamma 9V delta 2 T-cells was observed in the liver of HCVP patients, suggesting a functional impairment in the cytokine production in HCVP liver. Despite this hypo-responsiveness, intrahepatic V gamma 9V delta 2 T-cells are able to exert an anti-HCV activity after specific stimulation. Altogether, our data show that HCV infection induced a dysregulation of intrahepatic V gamma 9V delta 2 T cells that maintain their anti-HCV activity after specific stimulation. A study aimed to evaluate the mechanisms of the antiviral activity may be useful to identify new pathways able to improve V gamma 9V delta 2 T-cells intrahepatic function during HCV infection.