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Prepublished online as a Blood First Edition Paper on April 10, 2003; DOI 10.1182/blood-2002-07-2015. This Article Full Text Full Text (PDF) All Versions of this Article: 2002-07-2015v1 102/3/849    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map 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 Röth, A. Articles by Luiten, R. M. Search for Related Content PubMed PubMed Citation Articles by Röth, A. Articles by Luiten, R. M. Related Collections Immunobiology Gene Expression Gene Therapy Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 1 August 2003, Vol. 102, No. 3, pp. 849-857 GENE THERAPY Telomerase levels control the lifespan of human T lymphocytes Alexander Röth, Hans Yssel, Jérôme Pène, Elizabeth A. Chavez, Mike Schertzer, Peter M. Lansdorp, Hergen Spits, and Rosalie M. Luiten From the Terry Fox Laboratory, British Columbia Cancer Agency and University of British Columbia, Vancouver, Canada; Institut National de la Santé et de la Recherche Médicale (INSERM), Montpellier, France; and the Division of Immunology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands The loss of telomeric DNA with each cell division contributes to the limited replicative lifespan of human T lymphocytes. Although telomerase is transiently expressed in T lymphocytes upon activation, it is insufficient to confer immortality. We have previously shown that immortalization of human CD8+ T lymphocytes can be achieved by ectopic expression of the human telomerase reverse transcriptase (hTERT) gene, which encodes for the catalytic component of the telomerase complex. To study the role of endogenous hTERT in the lifespan of human T cells, we blocked endogenous hTERT expression by ectopic expression of dominant-negative (DN) hTERT. Cells expressing DN-hTERT had a decreased lifespan and showed cytogenetic abnormalities, including chromosome ends without detectable telomeric DNA as well as chromosome fusions. These results indicate that while endogenous hTERT cannot prevent overall telomere shortening, it has a major influence on the longevity of human T cells. Furthermore, we show that up-regulation of hTERT in T cells upon activation decreases over time in culture. Long-term–cultured T cells also show a decreased expression of c-myc upon activation, resulting in less c-myc–induced transcription of hTERT. Moreover, memory T cells, which have expanded in vivo upon antigen encounter, expressed a lower level of hTERT upon activation than naive cells from the same donor. The observed inverse correlation between telomerase levels and replicative history suggests that telomerase levels in T cells are limiting and increasingly insufficient to sustain their proliferation. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. Aubert and P. M. Lansdorp Telomeres and Aging Physiol Rev, April 1, 2008; 88(2): 557 - 579. [Abstract] [Full Text] [PDF] Y. Yang, J. An, and N.-p. Weng Telomerase Is Involved in IL-7-Mediated Differential Survival of Naive and Memory CD4+ T Cells J. Immunol., March 15, 2008; 180(6): 3775 - 3781. [Abstract] [Full Text] [PDF] R. D. Kilpatrick, T. 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