Functional Restoration of HCV-Specific CD8 T Cells by PD-1 Blockade Is Defined by PD-1 Expression and Compartmentalization

Nobuhiro Nakamoto, David E. Kaplan, Jennifer Coleclough, Yun Li, Mary E. Valiga, Mary Kaminski, Abraham Shaked, Kim Olthoff, Emma Gostick, David A. Price, Gordon J. Freeman, E. John Wherry, Kyong Mi Chang

Research output: Contribution to journalArticle

194 Citations (Scopus)

Abstract

Background & Aims: 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.

Original languageEnglish
JournalGastroenterology
Volume134
Issue number7
DOIs
Publication statusPublished - 2008 Jun
Externally publishedYes

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Hepacivirus
Cell Death
T-Lymphocytes
Ligands
CD8 Antigens
Virus Diseases
Liver
CTLA-4 Antigen
Death Domain Receptors
Immune System Diseases
Chronic Hepatitis C
Orthomyxoviridae
Human Herpesvirus 4
Liver Diseases
Flow Cytometry
Viruses
Antigens

ASJC Scopus subject areas

  • Gastroenterology

Cite this

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 A.; Freeman, Gordon J.; Wherry, E. John; Chang, Kyong Mi.

In: Gastroenterology, Vol. 134, No. 7, 06.2008.

Research output: Contribution to journalArticle

Nakamoto, N, Kaplan, DE, Coleclough, J, Li, Y, Valiga, ME, Kaminski, M, Shaked, A, Olthoff, K, Gostick, E, Price, DA, Freeman, GJ, Wherry, EJ & Chang, KM 2008, 'Functional Restoration of HCV-Specific CD8 T Cells by PD-1 Blockade Is Defined by PD-1 Expression and Compartmentalization', Gastroenterology, vol. 134, no. 7. https://doi.org/10.1053/j.gastro.2008.02.033
Nakamoto, Nobuhiro ; Kaplan, David E. ; Coleclough, Jennifer ; Li, Yun ; Valiga, Mary E. ; Kaminski, Mary ; Shaked, Abraham ; Olthoff, Kim ; Gostick, Emma ; Price, David A. ; Freeman, Gordon J. ; Wherry, E. John ; Chang, Kyong Mi. / Functional Restoration of HCV-Specific CD8 T Cells by PD-1 Blockade Is Defined by PD-1 Expression and Compartmentalization. In: Gastroenterology. 2008 ; Vol. 134, No. 7.
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abstract = "Background & Aims: 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.",
author = "Nobuhiro Nakamoto and Kaplan, {David E.} and Jennifer Coleclough and Yun Li and Valiga, {Mary E.} and Mary Kaminski and Abraham Shaked and Kim Olthoff and Emma Gostick and Price, {David A.} and Freeman, {Gordon J.} and Wherry, {E. John} and Chang, {Kyong Mi}",
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AU - Kaplan, David E.

AU - Coleclough, Jennifer

AU - Li, Yun

AU - Valiga, Mary E.

AU - Kaminski, Mary

AU - Shaked, Abraham

AU - Olthoff, Kim

AU - Gostick, Emma

AU - Price, David A.

AU - Freeman, Gordon J.

AU - Wherry, E. John

AU - Chang, Kyong Mi

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