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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. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-01-069112v1 110/3/928    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Petrovas, C. Articles by Koup, R. A Search for Related Content PubMed PubMed Citation Articles by Petrovas, C. Articles by Koup, R. A Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted January 22, 2007 Accepted April 10, 2007 SIV-specific CD8+T-cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection Constantinos Petrovas*, David A Price, Joseph Mattapallil, David R Ambrozak, Christof Geldmacher, Valentina Cecchinato, Monica Vaccari, Elzbieta Tryniszewska, Emma Gostick, Mario Roederer, Daniel C Douek, Sara H Morgan, Simon J Davis, Genoveffa Franchini, and Richard A Koup Immunology Laboratory, Vaccine Research Center, NIAID, NIH, Bethesda, MD, United States Human Immunology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD, United States ImmunoTechnology Section, Vaccine Research Center, NIAID, NIH, Bethesda, MD, United States Animal Models and Retroviral Vaccines Section, National Cancer Institute, NIH, Bethesda, MD, United States Nuffield Department of Medicine, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom * Corresponding author; email: petrovasc{at}mail.nih.gov. 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 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-1high CD8+ 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 to 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: C. Petrovas, B. Chaon, D. R. Ambrozak, D. A. Price, J. J. Melenhorst, B. J. Hill, C. Geldmacher, J. P. Casazza, P. K. Chattopadhyay, M. Roederer, et al. Differential Association of Programmed Death-1 and CD57 with Ex Vivo Survival of CD8+ T Cells in HIV Infection J. Immunol., July 15, 2009; 183(2): 1120 - 1132. [Abstract] [Full Text] [PDF] C. M. Bucks, J. A. Norton, A. C. Boesteanu, Y. M. Mueller, and P. D. 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Immunol., December 15, 2008; 181(12): 8215 - 8225. [Abstract] [Full Text] [PDF] R. C. Zahn, M. D. Rett, B. Korioth-Schmitz, Y. Sun, A. P. Buzby, S. Goldstein, C. R. Brown, R. A. Byrum, G. J. Freeman, N. L. Letvin, et al. Simian Immunodeficiency Virus (SIV)-Specific CD8+ T-Cell Responses in Vervet African Green Monkeys Chronically Infected with SIVagm J. Virol., December 1, 2008; 82(23): 11577 - 11588. [Abstract] [Full Text] [PDF] R. B. Jones, L. C. Ndhlovu, J. D. Barbour, P. M. Sheth, A. R. Jha, B. R. Long, J. C. Wong, M. Satkunarajah, M. Schweneker, J. M. Chapman, et al. Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection J. Exp. Med., November 24, 2008; 205(12): 2763 - 2779. [Abstract] [Full Text] [PDF] D. A. Hafler and V. Kuchroo TIMs: central regulators of immune responses J. Exp. Med., November 24, 2008; 205(12): 2699 - 2701. [Abstract] [Full Text] [PDF] S. D. Blackburn, H. Shin, G. J. 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