title: Persistent hepatitis C virus (HCV) infection impairs HCV-specific cytotoxic T cell reactivity through Mcl-1/Bim imbalance due to CD127 down-regulation.
abstract: 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 pro-apoptotic 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. 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 phenotype of HCV-specific CTLs was tested by staining detectable CD8(+)/pentamer(+) cells with anti-Mcl-1/Bim/CD127 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 analysed by flow cytometry. CD127(low)-expressing HCV-specific CTLs associated with high HCV viraemia, while CD127(high) correlated with undetectable viral loads (P < 0.001). Directly ex vivo, pentamer(+) cell frequency was similar according to CD127 expression level. Nevertheless, CD127(low) 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 CD127(low) 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). In summary, a low ex vivo Mcl-1 expression and Bim up-regulation after antigen encounter are involved in CD127(low) HCV-specific CTL hyporeactivity during chronic infection, but it can be overcome by apoptosis blockade.
authors.affiliation: Translational Hepatology Unit, Guadalajara University Hospital, University of Alcalá, Guadalajara, Spain. jlarrubiam@meditex.es
authors.forename: J R
authors.initials: JR
authors.lastname: Larrubia
authors.forename: M U
authors.initials: MU
authors.lastname: Lokhande
authors.forename: S
authors.initials: S
authors.lastname: García-Garzón
authors.forename: J
authors.initials: J
authors.lastname: Miquel
authors.forename: A
authors.initials: A
authors.lastname: González-Praetorius
authors.forename: T
authors.initials: T
authors.lastname: Parra-Cid
authors.forename: E
authors.initials: E
authors.lastname: Sanz-de-Villalobos
mesh_terms: D000328:Adult; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D049109:Cell Proliferation; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D015536:Down-Regulation; D005260:Female; D016174:Hepacivirus / Q000276:immunology* / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D054884:Host-Pathogen Interactions; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010641:Phenotype; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000502:physiology* / Q000821:virology; D014779:Virus Replication
chemical_list: D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D053699:Interleukin-7 Receptor alpha Subunit; D008565:Membrane Proteins; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D007371:Interferon-gamma