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

Abstract 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.