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Functional restoration of HCV-specific CD8 T Cells by PD-1 blockade is defined by PD-1 expression and compartmentalization

Nakamoto, Nobuhiro, Kaplan, David E., Coleclough, Jennifer, Li, Yun, Valiga, Mary E., Kaminski, Mary, Shaked, Abraham, Olthoff, Kim, Gostick, Emma, Price, David, Freeman, Gordon J., Wherry, E. John and Chang, Kyong-Mi 2008. Functional restoration of HCV-specific CD8 T Cells by PD-1 blockade is defined by PD-1 expression and compartmentalization. Gastroenterology 134 (7) , pp. 1927-1937. 10.1053/j.gastro.2008.02.033

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Abstract

The immunoinhibitory receptor programmed death-1 (PD-1) is up-regulated on dysfunctional virus-specific CD8 T cells during chronic viral infections, and blockade of PD-1/PD-ligand (PD-L) interactions can restore their function. As hepatitis C virus (HCV) persists in the liver with immune-mediated disease pathogenesis, we examined the role of PD-1/PD-L pathway in antigen-specific CD8 T-cell dysfunction in the liver and blood of HCV-infected patients. Methods: PD-1 expression and function of circulating CD8 T cells specific for HCV, Epstein–Barr virus, and influenza virus were examined ex vivo and following antigenic stimulation in vitro in patients with acute, chronic, and resolved HCV infection using class I tetramers and flow cytometry. Intrahepatic CD8 T cells were examined from liver explants of chronically HCV-infected transplant recipients. Results: Intrahepatic HCV-specific CD8 T cells from chronically HCV-infected patients were highly PD-1 positive, profoundly dysfunctional, and unexpectedly refractory to PD-1/PD-L blockade, contrasting from circulating PD-1–intermediate HCV-specific CD8 T cells with responsiveness to PD-1/PD-L blockade. This intrahepatic functional impairment was HCV-specific and directly associated with the level of PD-1 expression. Highly PD-1–positive intrahepatic CD8 T cells were more phenotypically exhausted with increased cytotoxic T-lymphocyte antigen 4 and reduced CD28 and CD127 expression, suggesting that active antigen-specific stimulation in the liver induces a profound functional exhaustion not reversible by PD-1/PD-L blockade alone. Conclusions: HCV-specific CD8 T-cell dysfunction and responsiveness to PD-1/PD-L blockade are defined by their PD-1 expression and compartmentalization. These findings provide new and clinically relevant insight to differential antigen-specific CD8 T-cell exhaustion and their functional restoration.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Systems Immunity Research Institute (SIURI)
Subjects: R Medicine > RZ Other systems of medicine
Publisher: Elsevier
ISSN: 0016-5085
Last Modified: 07 Mar 2019 22:04
URI: http://orca.cf.ac.uk/id/eprint/25143

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