HIV-Specific Cd8+ T Cells Produce Antiviral Cytokines but Are Impaired in Cytolytic Function

By V. Appay, D. Nixon, S. M. Donahoe, G. Gillespie, T. Dong, A. King, G. Ogg, H. Spiegel, C. Conlon, C. Spina and 6 more. Journal of Experimental Medicine, 2000

1,032 citations recorded by the source corpus.

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.

Subfields: Epidemiology, Immunology, Virology

View Paper: https://www.semanticscholar.org/paper/438983eef7525221b6b4200ae8f0f22264adc560

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Epidemiology

1. F. Sallusto
2. W. Zou

In Immunology

1. Mario Roederer
2. Daniel C. Douek
3. R. Koup
4. V. Appay
5. F. Sallusto
6. T. Welling
7. Joel Crespo
8. Zhigang Tian

In Virology

1. Daniel C. Douek
2. Mario Roederer
3. R. Koup
4. V. Appay
5. F. Sallusto

Citations in the corpus

• T cell anergy, exhaustion, senescence and stemness in the tumor microenvironment (2013, background): “In addition to phenotypic alteration, senescent T cells manifest defective killing abilities and the development of negative regulatory functions [52,53].”
• Phenotype and function of human T lymphocyte subsets: Consensus and issues (2008, background): “A potential link between failed T cell efficacy and an immature phenotype was initially suggested in that HIV-specific CD8 T cells show a CD271CCR72CD45RA2 phenotype in contrast to CMV-specific CD8 T cells (characterized by a CD272CCR72CD45RA1 phenotype) (61,62)”
• Analysis of Total Human Immunodeficiency Virus (HIV)-Specific CD4+ and CD8+ T-Cell Responses: Relationship to Viral Load in Untreated HIV Infection (2001, background): “Since the CD27 phenotype has been associated with functionally efficient CTL, it is possible that frequencies of HIV-specific CTL with this phenotype show a different relationship with viral load (4, 25).”
• Emerging Concepts in the Immunopathogenesis of AIDS (2009, neutral): “Despite evidence that HIV- and SIV-specific CD8 T cells (CTLs) are involved in the control of viral replication (81–83), they have intrinsic functional defects— including decreased cytokine production, decreased proliferation, lack of polyfunctionality (described above), and lack of full effector di”