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Blood, 1 August 2007, Vol. 110, No. 3, pp. 928-936. Prepublished online as a Blood First Edition Paper on April 17, 2007; DOI 10.1182/blood-2007-01-069112.
IMMUNOBIOLOGY SIV-specific CD8+ T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection1 Immunology Laboratory and 2 Human Immunology Section, Vaccine Research Center, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD; 3 Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom; 4 Department of Microbiology and Immunology, Uniformed Services University, Bethesda, MD; 5 Animal Models and Retroviral Vaccines Section, National Cancer Institute, NIH, Bethesda, MD; 6 ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD
Programmed death-1 (PD-1) is a critical mediator of virus-specific CD8+ T-cell exhaustion. Here, we examined the expression of PD-1 on simian immunodeficiency virus (SIV)-specific CD8+ T cells and its possible involvement in regulation of cytokine production, proliferation, and survival of these cells. The majority of SIV-specific CD8+ T cells expressed a PD-1high phenotype, independent of their differentiation status, in all tissues tested. PD-1 expression gradually declined on CD8+ T cells specific for SIV-derived epitopes that had undergone mutational escape, indicating that antigen-specific TCR stimulation is the primary determinant of PD-1 expression. SIV-specific PD-1highCD8+ T cells produced IFN-
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| Copyright © 2007 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
, TNF-
, and IL-2 under cognate peptide stimulation. While CD8+ T cells that proliferated in response to antigen had a PD-1high phenotype, it was determined that there was a reduced proliferative capacity of PD-1high compared with PD-1low SIV-specific CD8+ T cells. PD-1high SIV-specific CD8+ T cells were highly susceptible to cell death leading to loss of such cells after in vitro stimulation. Thus, PD-1 is a negative regulator of SIV-specific CD8+ T cells, operating predominantly through the induction of cell death. Manipulation of the interaction of PD-1 with its ligands could thus potentially restore the CD8+ T-cell responses in SIV infection. 
