Journal Article

Synergistic Reversal of Intrahepatic HCV-Specific CD8 T Cell Exhaustion by Combined PD-1/CTLA-4 Blockade

Kaminski, Mary, Gostick, Emma, Olthoff, Kim, Nakamoto, Nobuhiro, Shaked, Abraham, Freeman, Gordon J., Wherry, E. John, Chang, Kyong-Mi, Price, David A., Cho, Hyosun, Valiga, Mary E.

2009

Overview

Viral persistence is associated with hierarchical antiviral CD8 T cell exhaustion with increased programmed death-1 (PD-1) expression. In HCV persistence, HCV-specific CD8 T cells from the liver (the site of viral replication) display increased PD-1 expression and a profound functional impairment that is not reversed by PD-1 blockade alone. Here, we report that the inhibitory receptor cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is preferentially upregulated in PD-1(+) T cells from the liver but not blood of chronically HCV-infected patients. PD-1/CTLA-4 co-expression in intrahepatic T cells was associated with a profound HCV-specific effector dysfunction that was synergistically reversed by combined PD-1/CTLA-4 blockade in vitro, but not by blocking PD-1 or CTLA-4 alone. A similar effect was observed in circulating HCV-specific CD8 T cells with increased PD-1/CTLA-4 co-expression during acute hepatitis C. The functional response to combined blockade was directly associated with CTLA-4 expression, lost with CD28-depletion and CD4-independent (including CD4(+)FoxP3(+) Tregs). We conclude that PD-1 and CTLA-4 pathways both contribute to virus-specific T cell exhaustion at the site of viral replication by a redundant mechanism that requires combined PD-1/CTLA-4 blockade to reverse. These findings provide new insights into the mechanisms of virus-specific T cell dysfunction, and suggest that the synergistic effect by combined inhibitory receptor blockade might have a therapeutic application against chronic viral infection in vivo, provided that it does not induce autoimmunity.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Antigens, CD - metabolism / Antigens, Differentiation, T-Lymphocyte - metabolism / Apoptosis Regulatory Proteins - metabolism / Blood - immunology / CD28 Antigens - metabolism / CD8-Positive T-Lymphocytes - immunology / Chi-Square Distribution / CTLA-4 Antigen / Cytokines - metabolism / Female / Flow Cytometry / Forkhead Transcription Factors - metabolism / Gastroenterology and Hepatology/Hepatology / Genetic aspects / Hepacivirus - physiology / Hepatitis / Hepatitis C virus / Hepatitis C, Chronic - pathology / Hepatocytes / HIV / Human immunodeficiency virus / Humans / Immune response / Immunology/Immunity to Infections / Inducible T-Cell Co-Stimulator Protein / Infections / Liver - immunology / Male / Physiological aspects / Programmed Cell Death 1 Receptor / Receptors, Immunologic - metabolism / Statistics, Nonparametric / T cells / Viral infections / Virology/Immune Evasion / Virology/New Therapies, including Antivirals and Immunotherapy / Virology/Persistence and Latency