Blockade of PD-1/B7-H1 interaction restores effector CD8+ T cell responses in a hepatitis C virus core murine model.
The impaired function of CD8(+) T cells is characteristic of hepatitis C virus (HCV) persistent infection. HCV core protein has been reported to inhibit CD8(+) T cell responses. To determine the mechanism of the HCV core in suppressing Ag-specific CD8(+) T cell responses, we generated a transgenic mouse, core(+) mice, where the expression of core protein is directed to the liver using the albumin promoter. Using a recombinant adenovirus to deliver Ag, we demonstrated that core(+) mice failed to clear adenovirus-LacZ (Ad-LacZ) infection in the liver. The effector function of LacZ-specific CD8(+) T cells was particularly impaired in the livers of core(+) mice, with suppression of IFN-gamma, TNF-alpha, and granzyme B production by CD8(+) T cells. In addition, the impaired CD8(+) T cell responses in core(+) mice were accompanied by the enhanced expression of the inhibitory receptor programmed death-1 (PD-1) by LacZ-specific CD8(+) T cells and its ligand B7-H1 on liver dendritic cells following Ad-LacZ infection. Importantly, blockade of the PD-1/B7-H1 inhibitory pathway (using a B7-H1 blocking antibody) in core(+) mice enhanced effector function of CD8(+) T cells and cleared Ad-LacZ-infection as compared with that in mice treated with control Ab. This suggests that the regulation of the PD-1/B7-H1 inhibitory pathway is crucial for HCV core-mediated impaired T cell responses and viral persistence in the liver. This also suggests that manipulation of the PD-1/B7-H1 pathway may be a potential immunotherapy to enhance effector T cell responses during persistent HCV infection.
Lukens
John R
JR
Beirne Carter Center for Immunology Research, Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA.
Cruise
Michael W
MW
Lassen
Matthew G
MG
Hahn
Young S
YS
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000943:Antigens, Differentiation / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology*; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D017930:Genes, Reporter / Q000235:genetics; D016174:Hepacivirus / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006526:Hepatitis C / Q000276:immunology*; D008099:Liver / Q000166:cytology / Q000276:immunology; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000037:antagonists & inhibitors / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013154:Spleen / Q000276:immunology; D015854:Up-Regulation; D014758:Viral Core Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D014758:Viral Core Proteins; C069130:nucleocapsid protein, Hepatitis C virus