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 ORCID: https://orcid.org/0000-0001-9416-2737, 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:	06 May 2023 20:22
URI:	https://orca.cardiff.ac.uk/id/eprint/25143

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