Telomerase levels control the lifespan of XXXX T lymphocytes.

@entity1 @entity517 @entity3207 @entity2008 @entity2215
The loss of telomeric DNA with each cell division contributes to the limited replicative lifespan of @entity1 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 @entity1 CD8+ T lymphocytes can be achieved by ectopic expression of the @entity1 telomerase reverse transcriptase ( @entity2215 ) gene, which encodes for the catalytic component of the telomerase complex. To study the role of endogenous @entity2215 in the lifespan of @entity1 T cells, we blocked endogenous @entity2215 expression by ectopic expression of dominant-negative (DN) @entity2215 . Cells expressing DN- @entity2215 had a decreased lifespan and showed @entity2008 , including chromosome ends without detectable telomeric DNA as well as chromosome fusions. These results indicate that while endogenous @entity2215 cannot prevent overall telomere @entity3207 , it has a major influence on the longevity of @entity1 T cells. Furthermore, we show that up-regulation of @entity2215 in T cells upon activation decreases over time in culture. Long-term-cultured T cells also show a decreased expression of @entity517 upon activation, resulting in less @entity517 -induced transcription of @entity2215 . Moreover, memory T cells, which have expanded in vivo upon antigen encounter, expressed a lower level of @entity2215 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.
