Synergistic reversal of intrahepatic HCV-specific CD8 T cell exhaustion by combined PD-1/CTLA-4 blockade
Open accessAbstract
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.
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CTLA-4 signaling dampens immune responses against infections and tumor cells.
“CTLA-4 signaling has been shown to dampen immune responses against infections and tumor cells (28, 29).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [28]
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- Authors
- Nakamoto, N., Cho, H., Shaked, A., Olthoff, K., Valiga, M. E., Kaminski, M., Gostick, E., Price, D. A., Freeman, G. J., Wherry, E. J., & Chang, K.-M.
- Affiliations
- Philadelphia VA Medical Center (US)
- Hospital of the University of Pennsylvania (US)
- Cardiff University (GB)
- Harvard University (US)
- The Wistar Institute (US)
- Corresponding author
- Chang, Kyong-Mi
- ORCID
- Venue
- PLoS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2009-02-27
- Volume
- 5
- Issue
- 2
- Pages
- e1000313
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC2642724
- OpenAlex
- W2077940506
- Cited by
- 380
- References
- 55
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 13 · 2023: 12 · 2022: 11 · 2021: 16 · 2020: 23 · 2019: 24 · 2018: 17 · 2017: 23 · 2016: 21 · 2015: 27 · 2014: 41 · 2013: 29 · 2012: 24
- FWCI
- 22.69
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Pathogens (publishedVersion, public-domain)
- PubMed Central (publishedVersion, public-domain)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- Foundation for the National Institutes of Health (P30 CA016520)
- University of Pennsylvania (P30CA016520, M01-RR00040)
- American Gastroenterological Association
- Abramson Cancer Center (P30CA016520)
- National Institutes of Health (AI56299, RR00040, CA016520)
- Medical Research Council
- National Cancer Institute (CA016520, P30CA016520)
- National Institute of Allergy and Infectious Diseases (R01AI047519, AI47519, P01AI056299)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK50306, P30DK050306)
- National Center for Research Resources (M01-RR-00040, M01RR000040)
- Topics
- Health Sciences › Medicine › Hepatology › Hepatitis C virus research
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- hepatitis C virus, CD8+ T cell exhaustion, PD-1, CTLA-4, PD-1/CTLA-4 blockade, intrahepatic T cells, chronic viral infection, T cell dysfunction, regulatory T cells, CD28, acute hepatitis C, antiviral immunity
- MeSH terms
- Antigens, Differentiation, T-Lymphocyte, Blood, Female, Flow Cytometry, Humans, Liver, Male, Receptors, Immunologic, Antigens, CD, Chi-Square Distribution, Hepacivirus, Cytokines, CD28 Antigens, CD8-Positive T-Lymphocytes, Statistics, Nonparametric, Hepatitis C, Chronic, Hepatocytes, Apoptosis Regulatory Proteins, Forkhead Transcription Factors, Inducible T-Cell Co-Stimulator Protein, CTLA-4 Antigen, Programmed Cell Death 1 Receptor
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