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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.
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IMMUNOBIOLOGY
SIV-specific CD8+ T cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection
Constantinos Petrovas1,
David A. Price2,3,
Joseph Mattapallil4,
David R. Ambrozak1,
Christof Geldmacher1,
Valentina Cecchinato5,
Monica Vaccari5,
Elzbieta Tryniszewska5,
Emma Gostick3,
Mario Roederer6,
Daniel C. Douek2,
Sara H. Morgan3,
Simon J. Davis3,
Genoveffa Franchini5, and
Richard A. Koup1
1 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- , 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.
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