Telomerase levels control the lifespan of human T lymphocytes

Röth, Alexander; Yssel, Hans; Pène, Jérôme; Chavez, Elizabeth A.; Schertzer, Michael; Lansdorp, Peter M.; Spits, Hergen; Luiten, Rosalie M.

doi:10.1182/blood-2002-07-2015

Cited by 129 publications

(96 citation statements)

References 49 publications

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“…These data suggest that telomere elongation preferentially occurred on shorter telomeres, which is in agreement with observations in human hTERT-transfected fibroblast cells in vitro (24). In T lymphocytes transfection of dominant-negative hTERT led to loss of FISH-detectable telomere ends but no generalized telomere shortening suggesting a role for endogenous telomerase in maintaining critically short telomeres (25). Our data suggest a similar preference for elongation of short telomeres in B cells without forced expression of hTERT.…”

Section: Discussionsupporting

confidence: 80%

Telomere length and heredity: Indications of paternal inheritance

Nordfjäll

Larefalk

Lindgren

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

180

146

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Cellular telomere length is linked to replicative life span. Telomere repeats are lost in peripheral blood cells in vivo by age, and women show less telomere attrition than men. Previous reports have indicated that telomere length and chromosome-specific telomerelength patterns partly are inherited. The mode of heredity has not been clarified, but a link to the X chromosome was recently suggested. We analyzed peripheral mononuclear cells from 49 unrelated families for telomere length using a real-time PCR method. Short-term cultured Epstein-Barr virus-transformed lymphoblasts from the same individuals (n ‫؍‬ 130) were analyzed for ability to maintain telomere length and possible gender-linked inheritance. A statistically significant association between telomere lengths comparing father-son (P ‫؍‬ 0.011, n ‫؍‬ 20) and father-daughter (P ‫؍‬ 0.005, n ‫؍‬ 22) pairs was found. However, no correlation was observed between mother-daughter (P ‫؍‬ 0.463, n ‫؍‬ 23) or mother-son (P ‫؍‬ 0.577, n ‫؍‬ 18). The father-offspring correlation was highly significant (P < 0.0001), in contrast to mother-offspring (P ‫؍‬ 0.361). Epstein-Barr virus cultures demonstrated in most cases telomere preservation inversely related to initial mononuclear cell telomere length with short telomeres displaying the most pronounced elongation. Telomere length is inherited, and evidence for a father-to-offspring heritage of this trait was obtained, whereas in vitro telomere length maintenance was found to be dependent on the initial telomere length.gender S ince the demonstration of an association between telomere length and replicative potential (1-6), telomere biology has been in focus for issues on cellular senescence and immortalization. In human replicating somatic cells, there is an inverse relationship between telomere length and age, in cell cultures as well as at the organism level in vivo, albeit with a large interindividual variation. A strong association exists between critically short telomeres and induction of a senescence program leading to irreversible cell-cycle arrest, although telomere shortening is not an absolute requirement for senescence induction (7). True immortalization requires telomere maintenance, usually executed by the activity of telomerase or more rarely through recombinatorial events, as in ALT (alternative lengthening of telomeres) cells. The telomere reduction observed in normal peripheral mononuclear cells (MNCs) has been estimated to be 14-80 base pairs (bp) per year with some differences between various blood cell types (8-13). Because women have been found to lose fewer repeats per year than men, a gender difference in telomere attrition rate in blood cells has been proposed (10,14,15). Peripheral blood cell telomere length also has been found to be associated with cardiovascular diseases such as hypertension, atherosclerosis, and heart failure (16).Reports on monozygotic and dizygotic twins indicate that mean telomere length as well as chromosome-specific telomerelength patterns are in part inherited (17,18)...

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Section: Discussionsupporting

confidence: 80%

Telomere length and heredity: Indications of paternal inheritance

Nordfjäll

Larefalk

Lindgren

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

180

146

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“…20 Moreover, the lifespan of T cells has been shown to be regulated by the expression of hTERT. 30,31 p53 represses telomerase activity by downregulating hTERT expression in tumor lines. 32,33 Putting together our findings and results from other studies, the regulation of SAP, CD95, PUMA and hTERT by p53 and their role in the T cell survival/death, we hypothesize that p53 contributes to T cell homeostasis in several different ways, within a common network.…”

Section: Discussionmentioning

confidence: 99%

p53 contributes to T cell homeostasis through the induction of pro-apoptotic SAP

et al. 2012

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“…Comparable to other senescent cells, in vitro exhausted T cells have short telomeres, cannot proliferate even in the presence of co‐stimulatory molecules, and are resistant to apoptosis and metabolically active. This cell cycle arrest can be overcome by ectopic expression of the catalytic subunit of the telomerase (hTERT), demonstrating a role for telomere erosion in this process (Roth et al ., 2003). However, exhausted T cells seem to be distinct from senescent T cells because they have low expression of immunological markers of senescence and progressively lose the ability to secrete cytokines in contrast to senescent T cells (Wherry, 2011; Crespo et al ., 2013).…”

Section: Cellular Senescence and Immune Cell Fate Decisionmentioning

confidence: 99%

Cellular senescence impact on immune cell fate and function

et al. 2016

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SummaryCellular senescence occurs not only in cultured fibroblasts, but also in undifferentiated and specialized cells from various tissues of all ages, in vitro and in vivo. Here, we review recent findings on the role of cellular senescence in immune cell fate decisions in macrophage polarization, natural killer cell phenotype, and following T‐lymphocyte activation. We also introduce the involvement of the onset of cellular senescence in some immune responses including T‐helper lymphocyte‐dependent tissue homeostatic functions and T‐regulatory cell‐dependent suppressive mechanisms. Altogether, these data propose that cellular senescence plays a wide‐reaching role as a homeostatic orchestrator.

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Telomerase levels control the lifespan of human T lymphocytes

Cited by 129 publications

References 49 publications

Telomere length and heredity: Indications of paternal inheritance

Telomere length and heredity: Indications of paternal inheritance

p53 contributes to T cell homeostasis through the induction of pro-apoptotic SAP

Cellular senescence impact on immune cell fate and function

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