title: 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.
authors.affiliation: Translational Hepatology Unit, Guadalajara University Hospital, University of Alcalá, Donante de Sangre st., 19002 Guadalajara, Spain. jlarrubiam@meditex.es
authors.forename: Juan R
authors.initials: JR
authors.lastname: Larrubia
authors.forename: Selma
authors.initials: S
authors.lastname: Benito-Martínez
authors.forename: Joaquín
authors.initials: J
authors.lastname: Miquel
authors.forename: Miryam
authors.initials: M
authors.lastname: Calvino
authors.forename: Eduardo
authors.initials: E
authors.lastname: Sanz-de-Villalobos
authors.forename: Alejandro
authors.initials: A
authors.lastname: González-Praetorius
authors.forename: Sonia
authors.initials: S
authors.lastname: Albertos
authors.forename: Silvia
authors.initials: S
authors.lastname: García-Garzón
authors.forename: Megha
authors.initials: M
authors.lastname: Lokhande
authors.forename: Trinidad
authors.initials: T
authors.lastname: Parra-Cid
mesh_terms: D000328:Adult; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D060890:B7-H1 Antigen; D000072224:Bcl-2-Like Protein 11; D002452:Cell Count; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism*; D008099:Liver / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D018655:Lymphocyte Count; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019562:Viral Load / Q000276:immunology; D017361:Viral Nonstructural Proteins / Q000276:immunology; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000590:Amino Acid Chloromethyl Ketones; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; D000072224:Bcl-2-Like Protein 11; D053699:Interleukin-7 Receptor alpha Subunit; D008565:Membrane Proteins; D061026:Programmed Cell Death 1 Receptor; D011518:Proto-Oncogene Proteins; D017361:Viral Nonstructural Proteins; C000606775:BCL2L11 protein, human; C423236:CD274 protein, human; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C105992:PDCD1 protein, human; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone