title: Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade.
abstract: Viral persistence is associated with hierarchical antiviral CD8 T cell exhaustion with increased programmed death-1 (PD-1) expression. In HCV persistence, HCV-specific CD8 T cells from the liver (the site of viral replication) display increased PD-1 expression and a profound functional impairment that is not reversed by PD-1 blockade alone. Here, we report that the inhibitory receptor cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is preferentially upregulated in PD-1(+) T cells from the liver but not blood of chronically HCV-infected patients. PD-1/CTLA-4 co-expression in intrahepatic T cells was associated with a profound HCV-specific effector dysfunction that was synergistically reversed by combined PD-1/CTLA-4 blockade in vitro, but not by blocking PD-1 or CTLA-4 alone. A similar effect was observed in circulating HCV-specific CD8 T cells with increased PD-1/CTLA-4 co-expression during acute hepatitis C. The functional response to combined blockade was directly associated with CTLA-4 expression, lost with CD28-depletion and CD4-independent (including CD4(+)FoxP3(+) Tregs). We conclude that PD-1 and CTLA-4 pathways both contribute to virus-specific T cell exhaustion at the site of viral replication by a redundant mechanism that requires combined PD-1/CTLA-4 blockade to reverse. These findings provide new insights into the mechanisms of virus-specific T cell dysfunction, and suggest that the synergistic effect by combined inhibitory receptor blockade might have a therapeutic application against chronic viral infection in vivo, provided that it does not induce autoimmunity.
authors.affiliation: Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, USA.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Nakamoto
authors.forename: Hyosun
authors.initials: H
authors.lastname: Cho
authors.forename: Abraham
authors.initials: A
authors.lastname: Shaked
authors.forename: Kim
authors.initials: K
authors.lastname: Olthoff
authors.forename: Mary E
authors.initials: ME
authors.lastname: Valiga
authors.forename: Mary
authors.initials: M
authors.lastname: Kaminski
authors.forename: Emma
authors.initials: E
authors.lastname: Gostick
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.forename: Kyong-Mi
authors.initials: KM
authors.lastname: Chang
mesh_terms: D015703:Antigens, CD / Q000378:metabolism*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001769:Blood / Q000276:immunology; D018106:CD28 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen; D016009:Chi-Square Distribution; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016174:Hepacivirus / Q000502:physiology; D019698:Hepatitis C, Chronic / Q000473:pathology*; D022781:Hepatocytes; D006801:Humans; D060889:Inducible T-Cell Co-Stimulator Protein; D008099:Liver / Q000276:immunology; D008297:Male; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic / Q000378:metabolism; D018709:Statistics, Nonparametric
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D051017:Apoptosis Regulatory Proteins; C482586:BTLA protein, human; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C556692:ICOS protein, human; D060889:Inducible T-Cell Co-Stimulator Protein; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic