The Journal of Experimental Medicine
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Published online 5 September 2006 doi:10.1084/jem.20061496
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 10, 2281-2292
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ARTICLE

 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

CORRESPONDENCE Richard A. Koup: rkoup{at}mail.nih.gov

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.

Abbreviations used: mDC, myeloid dendritic cell; PD, programmed death; pDC, plasmacytoid dendritic cell; PD-L, programmed death ligand; TLR, toll-like receptor; VV, vaccinia virus.


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