Functional restoration of HCV-specific CD8 T cells by PD-1 blockade is defined by PD-1 expression and compartmentalization.
OBJECTIVE
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.
Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Nobuhiro
N
Nakamoto
David E
DE
Kaplan
Jennifer
J
Coleclough
Yun
Y
Li
Mary E
ME
Valiga
Mary
M
Kaminski
Abraham
A
Shaked
Kim
K
Olthoff
Emma
E
Gostick
David A
DA
Price
Gordon J
GJ
Freeman
E John
EJ
Wherry
Kyong-Mi
KM
Chang
D000208:Acute Disease; D000328:Adult; D000911:Antibodies, Monoclonal; D015703:Antigens, CD / Q000097:blood / Q000378:metabolism*; D000998:Antiviral Agents / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000097:blood / Q000378:metabolism*; D060890:B7-H1 Antigen; D018106:CD28 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology*; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D002451:Cell Compartmentation / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D016174:Hepacivirus / Q000276:immunology*; D006526:Hepatitis C / Q000276:immunology* / Q000628:therapy; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000628:therapy; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000821:virology*; D016031:Liver Transplantation; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D010414:Pennsylvania; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor
D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000998:Antiviral Agents; D051017:Apoptosis Regulatory Proteins; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D015395:Histocompatibility Antigens Class I; D053699:Interleukin-7 Receptor alpha Subunit; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor