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

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

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Title: Synergistic Reversal of Intrahepatic HCV-Specific CD8 T Cell Exhaustion by Combined PD-1/CTLA-4 Blockade
Author: Nakamoto, Nobuhiro; Cho, Hyosun; Shaked, Abraham; Olthoff, Kim; Valiga, Mary E.; Kaminski, Mary; Gostick, Emma; Price, David A.; Freeman, Gordon James; Wherry, E. John; Chang, Kyong-Mi

Note: Order does not necessarily reflect citation order of authors.

Citation: Nakamoto, Nobuhiro, Hyosun Cho, Abraham Shaked, Kim Olthoff, Mary E. Valiga, Mary Kaminski, Emma Gostick, et al. 2009. Synergistic reversal of intrahepatic HCV-specific CD8 T Cell exhaustion by combined PD-1/CTLA-4 blockade. PLoS Pathogens 5(2): e1000313.
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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.
Published Version: doi://10.1371/journal.ppat.1000313
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2642724/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10021580

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