Bim-mediated apoptosis and PD-1/PD-L1 pathway impair reactivity of PD1+/CD127− HCV-specific CD8+ cells targeting the virus in chronic hepatitis C virus infection

PD-1 molecule promotes anergy and IL-7 receptor (CD127) induces an anti-apoptotic effect on T cells. Correlation between PD-1/CD127 phenotype and hepatitis C virus (HCV)-specific CD8+ cell reactivity in resolved infection (RI) after treatment and persistent HCV-infection (PI) was analysed. Directly ex vivo, PD-1 and CD127 expression on HCV-specific CD8+ cells displayed a positive and negative correlation, respectively with viraemia. Proliferation after stimulation on PD-1−/CD127+ cells from RI cases was preserved, while it was impaired on PD-1+/CD127− cells from PI patients. PD1+/CD127+ population was observed in PI, and these maintained expansion ability but they did not target the virus. Frequency of PI cases with HCV-specific CD8+ cell proliferation increased after anti-PD-L1 and anti-apoptotic treatment. Bim expression on HCV-specific CD8+ cells from PI patients was enhanced. In conclusion, during chronic HCV infection non-reactive HCV-specific CD8+ cells targeting the virus are PD-1+/CD127−/Bim+ and, blocking apoptosis and PD-1/PD-L1 pathway on them enhances in vitro reactivity.