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Synergistic reversal of intrahepatic hcv-specific cd8 t cell exhaustion by combined pd-1/ctla-4 blockade

Nakamoto, Nobuhiro, Cho, Hyosun, Shaked, Abraham, Olthoff, Kim, Valiga, Mary E., Kaminski, Mary, Gostick, Emma, Price, David, Freeman, Gordon J., Wherry, E. John and Chang, Kyong-Mi 2009. Synergistic reversal of intrahepatic hcv-specific cd8 t cell exhaustion by combined pd-1/ctla-4 blockade. PLoS Pathogens 5 (2) , e1000313. 10.1371/journal.ppat.1000313

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Abstract

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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: Q Science > QR Microbiology > QR180 Immunology
R Medicine > R Medicine (General)
R Medicine > RB Pathology
Publisher: Public Library of Science
ISSN: 1553-7374
Date of First Compliant Deposit: 30 March 2016
Last Modified: 08 Oct 2019 04:02
URI: http://orca.cf.ac.uk/id/eprint/28798

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