Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade

Nobuhiro Nakamoto, Hyosun Cho, Abraham Shaked, Kim Olthoff, Mary E. Valiga, Mary Kaminski, Emma Gostick, David A. Price, Gordon J. Freeman, E. John Wherry, Kyong Mi Chang

Research output: Contribution to journalArticle

222 Citations (Scopus)

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.

Original languageEnglish
Article numbere1000313
JournalPLoS Pathogens
Volume5
Issue number2
DOIs
Publication statusPublished - 2009 Feb
Externally publishedYes

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CTLA-4 Antigen
T-Lymphocytes
Viruses
Liver
Virus Diseases
Hepatitis C
Autoimmunity
Antiviral Agents

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. / Nakamoto, Nobuhiro; Cho, Hyosun; Shaked, Abraham; Olthoff, Kim; Valiga, Mary E.; Kaminski, Mary; Gostick, Emma; Price, David A.; Freeman, Gordon J.; Wherry, E. John; Chang, Kyong Mi.

In: PLoS Pathogens, Vol. 5, No. 2, e1000313, 02.2009.

Research output: Contribution to journalArticle

Nakamoto, N, Cho, H, Shaked, A, Olthoff, K, Valiga, ME, Kaminski, M, Gostick, E, Price, DA, Freeman, GJ, Wherry, EJ & Chang, KM 2009, 'Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade', PLoS Pathogens, vol. 5, no. 2, e1000313. https://doi.org/10.1371/journal.ppat.1000313
Nakamoto, Nobuhiro ; Cho, Hyosun ; Shaked, Abraham ; Olthoff, Kim ; Valiga, Mary E. ; Kaminski, Mary ; Gostick, Emma ; Price, David A. ; Freeman, Gordon J. ; Wherry, E. John ; Chang, Kyong Mi. / Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade. In: PLoS Pathogens. 2009 ; Vol. 5, No. 2.
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