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

PLoS Pathogens

Kyong-Mi Chang¹  E. John Wherry¹  Mary E. Valiga²  Mary Kaminski²  Gordon J. Freeman²  Hyosun Cho³  David A. Price³  Kim Olthoff³  Abraham Shaked⁴  Emma Gostick⁴  Nobuhiro Nakamoto⁴ 

[1]Department of Medical Biochemistry and Immunology, Cardiff University School of Medicine, Cardiff, United Kingdom

[2]Department of Surgery, Penn Liver Transplant Center, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, United States of America

[3]Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, United States of America

[4]Philadelphia Veterans Affairs Medical Center, Philadelphia, Pennsylvania, United States of America

关键词: T cells;    Cytotoxic T cells;    Hepatitis C virus;    Blood;    T helper cells;    Flow cytometry;    Lymphocytes;    Regulatory T cells;   

DOI  :  10.1371/journal.ppat.1000313

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY