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

• Published in: Cellular immunology Vol. 269; no. 2; pp. 104 - 114
• Main Authors: Larrubia, Juan R., Benito-Martínez, Selma, Miquel, Joaquín, Calvino, Miryam, Sanz-de-Villalobos, Eduardo, González-Praetorius, Alejandro, Albertos, Sonia, García-Garzón, Silvia, Lokhande, Megha, Parra-Cid, Trinidad
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 2011
• Subjects: Adult; Amino Acid Chloromethyl Ketones - pharmacology; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antigens, CD - immunology; Antigens, CD - metabolism; Apoptosis; Apoptosis - drug effects; Apoptosis - immunology; Apoptosis Regulatory Proteins - metabolism; B7-H1 Antigen; Bcl-2-Like Protein 11; Bim; CD127; Cell Count; Cell Proliferation - drug effects; Chronic hepatitis; Cytotoxic T lymphocytes; Female; HCV; Hepatitis C virus; Hepatitis C, Chronic - immunology; Humans; Immunophenotyping; Interleukin-7 Receptor alpha Subunit - metabolism; Liver - immunology; Liver - pathology; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocyte Count; Male; Membrane Proteins - metabolism; Middle Aged; PD-1; PD-L1; Programmed Cell Death 1 Receptor; Proto-Oncogene Proteins - metabolism; Signal Transduction - drug effects; Signal Transduction - immunology; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - physiology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; T-Lymphocytes, Cytotoxic - pathology; Viral Load - immunology; Viral Nonstructural Proteins - immunology; Viral persistence; z-VAD-fmk; z-VAD-fmk; Chronic hepatitis; Bim; PD-L1; HCV; CD127; Viral persistence; PD-1; Cytotoxic T lymphocytes; Apoptosis
• ISSN: 0008-8749; 1090-2163
• DOI: 10.1016/j.cellimm.2011.03.011

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.