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Prepublished online as a Blood First Edition Paper on April 10, 2003; DOI 10.1182/blood-2002-07-2015.
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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.
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