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Blood, 15 July 2005, Vol. 106, No. 2, pp. 558-565. Prepublished online as a Blood First Edition Paper on March 29, 2005; DOI 10.1182/blood-2004-11-4469. This Article Full Text (PDF) All Versions of this Article: 2004-11-4469v1 106/2/558    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 Dunne, P. J Articles by Akbar, A. N Search for Related Content PubMed PubMed Citation Articles by Dunne, P. J Articles by Akbar, A. N Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted December 6, 2004 Accepted February 28, 2005 Quiescence and functional re-programming of Epstein-Barr Virus (EBV)-specific CD8+ T cells during persistent infection Padraic J Dunne, Lavina Belaramani, Jean M Fletcher, Silvia Fernandez de Mattos, Maria Lawrenz, Maria Vieira D. Soares, Malcolm H Rustin, Eric W Lam, Mike Salmon, and Arne N Akbar* Division of Infection and Immunity, University College London, London, United Kingdom Division of Medicine, Cancer Medicine UK Laboratories, Department of Cancer Medicine, Imperial College London, Hammersmith Hospital London, London, United Kingdom Department of Dermatology, HIV Research Unit, and Department of Chemical Pathology and Human Metabolism, Royal Free Hospital, London, United Kingdom Medical Research Council Center for Immune Regulation, Birmingham University, Birmingham, United Kingdom * Corresponding author; email: a.akbar{at}ucl.ac.uk. After acute infection Epstein-Barr virus (EBV)-specific memory CD8+ T cells exit cell cycle and a proportion of these antigen-experienced cells re-express CD45RA. However the signals involved are not known. We investigated the roles of IL-15 and IFN-/ (IFN-I) in these processes, since these mediators have a crucial but undefined role in the maintenance of CD8+ T cell memory. We show that IFN-I ( but not IL-15) allows activated EBV-specific CD8+ T cells to leave cell cycle without entering apoptosis. This was associated with up-regulation of the cyclin inhibitor p27, but not of CD45RA. In contrast, IL-15 (but not IFN-I ) induced 'homeostatic' proliferation and CD45RA re-expression by these cells in vitro. Different signals therefore induce quiescence and CD45RA re-expression in activated EBV-specific CD8+ T cells. After TCR activation freshly isolated CD45RA+ antigen-experienced CD8+ T cells show highly restricted proliferative activity but are highly cytotoxic and secrete IFN- efficiently. This suggests functional re-programming towards effector function but away from proliferation. The induction of quiescence and the generation of proliferation-independent effector CD8+ T cells that re-express CD45RA may minimize the impact of replicative senescence in virus-specific populations that would otherwise occur during decades of persistent infection. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: E. C. P. Waller, N. McKinney, R. Hicks, A. J. Carmichael, J. G. P. Sissons, and M. R. Wills Differential costimulation through CD137 (4 1BB) restores proliferation of human virus-specific "effector memory" (CD28 CD45RAHI) CD8+ T cells Blood, December 15, 2007; 110(13): 4360 - 4366. [Abstract] [Full Text] [PDF] N. Tatsis, J. C. Fitzgerald, A. Reyes-Sandoval, K. C. Harris-McCoy, S. E. Hensley, D. Zhou, S.-W. Lin, A. Bian, Z. Q. Xiang, A. Iparraguirre, et al. Adenoviral vectors persist in vivo and maintain activated CD8+ T cells: implications for their use as vaccines Blood, September 15, 2007; 110(6): 1916 - 1923. [Abstract] [Full Text] [PDF] F. J. Plunkett, O. Franzese, H. M. Finney, J. M. Fletcher, L. L. Belaramani, M. Salmon, I. Dokal, D. Webster, A. D. G. Lawson, and A. N. Akbar The Loss of Telomerase Activity in Highly Differentiated CD8+CD28-CD27- T Cells Is Associated with Decreased Akt (Ser473) Phosphorylation J. Immunol., June 15, 2007; 178(12): 7710 - 7719. [Abstract] [Full Text] [PDF] J. W. Northfield, C. P. Loo, J. D. Barbour, G. Spotts, F. M. Hecht, P. Klenerman, D. F. Nixon, and J. Michaelsson Human Immunodeficiency Virus Type 1 (HIV-1)-Specific CD8+ TEMRA Cells in Early Infection Are Linked to Control of HIV-1 Viremia and Predict the Subsequent Viral Load Set Point J. Virol., June 1, 2007; 81(11): 5759 - 5765. [Abstract] [Full Text] [PDF] A. N. Akbar and M. Vukmanovic-Stejic Telomerase in T Lymphocytes: Use It and Lose It? J. Immunol., June 1, 2007; 178(11): 6689 - 6694. [Abstract] [Full Text] [PDF] F. Bihl, M. Narayan, J. V. Chisholm III, L. M. Henry, T. J. Suscovich, E. E. Brown, T. M. Welzel, D. E. Kaufmann, T. M. Zaman, S. Dollard, et al. Lytic and Latent Antigens of the Human Gammaherpesviruses Kaposi's Sarcoma-Associated Herpesvirus and Epstein-Barr Virus Induce T-Cell Responses with Similar Functional Properties and Memory Phenotypes J. Virol., May 1, 2007; 81(9): 4904 - 4908. [Abstract] [Full Text] [PDF] J. Carrasco, D. Godelaine, A. Van Pel, T. Boon, and P. van der Bruggen CD45RA on human CD8 T cells is sensitive to the time elapsed since the last antigenic stimulation Blood, November 1, 2006; 108(9): 2897 - 2905. [Abstract] [Full Text] [PDF]

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