Following on from the last posting, another paper has now been published regarding PD-1 expression on HIV-specific CD8 T cells. Researchers from the Vaccine Research Center at the National Institutes of Health report broadly similar findings to the previous two papers although they also report that the upregulation of PD-1 on HIV-specific CD8 T cells significantly increases the sensitivity of these cells to apoptosis (programmed cell death). Blocking PD-L1 in vitro increased HIV-specific CD8 T cell proliferation and thereby increased the number of HIV-specific CD8 T cells capable of making a broad array of cytokines. However, unlike the prior papers, the VRC researcher's findings suggest that expression of PD-1 does not directly correlate with an inability to produce these cytokines.
The researchers conclude that: "Overall, our data demonstrate that PD-1 is preferentially expressed on CD8+ T cells specific for chronic viruses, and that PD-1 interaction with its ligands can regulate the ability of these virus-specific CD8+ T cells to survive and proliferate. Therefore, manipulation of this axis may lead to at least partial restoration of antigen-specific cell numbers and function in chronic viral infections such as HIV. It is important to remember that our data do not support the ability of PD-1 manipulation to restore all of the T cell functions that define functional 'exhaustion'."
Published online 5 September 2006. doi:10.1084/jem.20061496
The Journal of Experimental Medicine
PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection
Constantinos Petrovas1, Joseph P. Casazza1, Jason M. Brenchley2, David A. Price2,3, Emma Gostick3, William C. Adams1, Melissa L. Precopio1, Timothy Schacker4, Mario Roederer5, Daniel C. Douek2, and Richard A. Koup1
1 Immunology Laboratory, 2 Human Immunology Section, and 5 ImmunoTechnology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892
3 Nuffield Department of Clinical Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK
4 Department of Medicine, University of Minnesota, Minneapolis, MN 55455
Here, we report on the expression of programmed death (PD)-1 on human virus-specific CD8+ T cells and the effect of manipulating signaling through PD-1 on the survival, proliferation, and cytokine function of these cells. PD-1 expression was found to be low on naive CD8+ T cells and increased on memory CD8+ T cells according to antigen specificity. Memory CD8+ T cells specific for poorly controlled chronic persistent virus (HIV) more frequently expressed PD-1 than memory CD8+ T cells specific for well-controlled persistent virus (cytomegalovirus) or acute (vaccinia) viruses. PD-1 expression was independent of maturational markers on memory CD8+ T cells and was not directly associated with an inability to produce cytokines. Importantly, the level of PD-1 surface expression was the primary determinant of apoptosis sensitivity of virus-specific CD8+ T cells. Manipulation of PD-1 led to changes in the ability of the cells to survive and expand, which, over several days, affected the number of cells expressing cytokines. Therefore, PD-1 is a major regulator of apoptosis that can impact the frequency of antiviral T cells in chronic infections such as HIV, and could be manipulated to improve HIV-specific CD8+ T cell numbers, but possibly not all functions in vivo.
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