La infección persistente por el virus de la hepatitis C (VHC) altera la reactividad de las células citotóxicas VHC específicas mediante el desequilibrio entre Mcl-1 y Bim debido a la disminución de la expresión de CD127

Abstract

Background: In persistent hepatitis C virus (HCV) infection, HCV-specific cytotoxic T lymphocyte (CTL) reactivity is impaired and this affects HCV control. Interleukin-7 receptor (CD127) expression on these cells could regulate CTL reactivity through Mcl-1/Bim balance modulation. Bim is a proapoptotic molecule blocked by the action of Mcl-1. Mcl-1/Bim expression and T cell reactivity on HCV-specific CTLs were compared according to CD127 phenotype. Materials and Methods: Peripheral blood lymphocytes (PBL) from HLA-A2+ HCV+ patients were obtained. HCV-specific CTLs were visualized by staining PBL with anti-CD8 and HLA-A2/peptide pentameric complexes (pentamer). Mcl-1/Bim/CD127/IFN-! phenotype of HCV-specific CTLs was tested by staining detectable CD8+/pentamer+ cells with anti-Mcl-1/Bim/CD127/IFN-! antibodies. HCV-specific CTL proliferation ability after specific in vitro challenge was tested in the presence and absence of pancaspase inhibitor z-VAD-fmk. All stained cells were analyzed by flow cytometry. Results: CD127low-expressing HCV-specific CTLs associated with high HCV viraemia, while CD127high correlated with undetectable viral loads (P < 0.001). Directly ex vivo, pentamer+ cell frequency was similar according to CD127 expression level. Nevertheless, CD127low pentamer+ cell proliferation after specific in vitro challenge was impaired (P < 0.05), although this was corrected by z-VAD-fmk treatment (P < 0.05). Mcl-1 expression was low directly ex vivo (P < 0.01), and Bim was up regulated after antigen encounter (P < 0.05) of CD127low pentamer+ cells. The ex vivo difference between Mcl-1 and Bim expression on pentamer+ cells correlated positively with CD127 expression level (P < 0.001) and with pentamer+ cell reactivity (P < 0.05). The frequency directly ex vivo of IFN-!-producing pentamer+ cells was lower in CD127low group than in CD127high group (P<0.05). Conclusion: A low ex vivo Mcl-1 expression and Bim up-regulation after antigen encounter are involved in CD127low HCV-specific CTL hyporeactivity during chronic infection, but it can be overcome by apoptosis blockade.