HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function
Open accessAbstract
The use of peptide–human histocompatibility leukocyte antigen (HLA) class I tetrameric complexes to identify antigen-specific CD8+ T cells has provided a major development in our understanding of their role in controlling viral infections. However, questions remain about the exact function of these cells, particularly in HIV infection. Virus-specific cytotoxic T lymphocytes exert much of their activity by secreting soluble factors such as cytokines and chemokines. We describe here a method that combines the use of tetramers and intracellular staining to examine the functional heterogeneity of antigen-specific CD8+ T cells ex vivo. After stimulation by specific peptide antigen, secretion of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, macrophage inflammatory protein (MIP)-1β, and perforin is analyzed by FACS® within the tetramer-positive population in peripheral blood. Using this method, we have assessed the functional phenotype of HIV-specific CD8+ T cells compared with cytomegalovirus (CMV)-specific CD8+ T cells in HIV chronic infection. We show that the majority of circulating CD8+ T cells specific for CMV and HIV antigens are functionally active with regards to the secretion of antiviral cytokines in response to antigen, although a subset of tetramer-staining cells was identified that secretes IFN-γ and MIP-1β but not TNF-α. However, a striking finding is that HIV-specific CD8+ T cells express significantly lower levels of perforin than CMV-specific CD8+ T cells. This lack of perforin is linked with persistent CD27 expression on HIV-specific cells, suggesting impaired maturation, and specific lysis ex vivo is lower for HIV-specific compared with CMV-specific cells from the same donor. Thus, HIV-specific CD8+ T cells are impaired in cytolytic activity.
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Senescent T cells have defective killing abilities and develop negative regulatory functions.
“In addition to phenotypic alteration, senescent T cells manifest defective killing abilities and the development of negative regulatory functions [52,53].”
From T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment (2013) · cites this paper as [52]
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- Authors
- Appay, V., Nixon, D. F., Donahoe, S. M., Gillespie, G. M. A., Dong, T., King, A., Ogg, G. S., Spiegel, H. M. L., Conlon, C., Spina, C. A., Havlir, D. V., Richman, D. D., Waters, A., Easterbrook, P., McMichael, A. J., & Rowland-Jones, S. L.
- Affiliations
- John Radcliffe Hospital (GB)
- Aaron Diamond AIDS Research Center (US)
- University of California San Diego (US)
- National Health Service (GB)
- aMedical Research Council Human Immunology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DS, United Kingdom
- ORCID
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2000-07-03
- Volume
- 192
- Issue
- 1
- Pages
- 63-76
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC1887711
- OpenAlex
- W2119232577
- Cited by
- 871
- References
- 51
- Citations by year
- 2026: 3 · 2025: 12 · 2024: 18 · 2023: 7 · 2022: 12 · 2021: 6 · 2020: 9 · 2019: 15 · 2018: 9 · 2017: 8 · 2016: 7 · 2015: 14 · 2014: 16 · 2013: 21 · 2012: 23
- FWCI
- 29.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
- Funders
- King's College London
- National Institutes of Health
- Center for AIDS Research, University of Washington
- Medical Research Council
- National Institute of Allergy and Infectious Diseases (R01-AI44595, R01AI044595)
- Topics
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- HIV-specific CD8+ T cells, cytotoxic T lymphocytes, perforin, antiviral cytokines, interferon-gamma, TNF-α, MIP-1β, T cell development, cytomegalovirus-specific T cells, chronic HIV infection, T cell functional heterogeneity
- MeSH terms
- Clone Cells, Cytomegalovirus, Flow Cytometry, HIV, Humans, Interferon-gamma, Reference Values, T-Lymphocytes, Cytotoxic, Tumor Necrosis Factor-alpha, Histocompatibility Antigens Class I, HIV Infections, Cytokines, HIV Seronegativity, CD8-Positive T-Lymphocytes, Macrophage Inflammatory Proteins, Chemokine CCL4
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