Decreased proliferative capacity and increased susceptibility to activation-induced cell death in late-passage human cd4+ tcr2+ cultured T cell clones

Pawelec, Graham; Sansom, David M.; Rehbein, Arnika; Adibzadeh, Medi; Beckman, Ian

doi:10.1016/s0531-5565(96)00097-6

Cited by 62 publications

(32 citation statements)

References 29 publications

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“…It was therefore suggested that differential susceptibility to apoptosis late after T cell stimulation might contribute to explaining the preponderance of CD45RO+ cells in the elderly, although the differences actually measured in these studies were minimal (46.0 +/-4.5% versus 57.6 +/-6.1, P < 0.01, but n = only 7 in each group, with wide inter-individual variation and no information given on donor selection criteria). Lack of enhanced susceptibility of CD45RO+ cells to apoptosis is also contrary to findings noted above in vitro and in vivo (107,332,340), and careful inspection of the data in the above publication revealed that there was in fact a greater degree of susceptibility to apoptosis by CD45RO+ cells in the elderly as well (27%-versus-36% respectively, a difference of 9% compared to 11% in the RO-negatives; hardly an impressive difference).…”

Section: Activation-induced Cell Death and Agingmentioning

confidence: 69%

“…Interestingly, the faster recovery of CD45RO+ cells shortly after chemotherapy (3 -6 months) was followed by another decrease in these cells, at 9-12 months; this was due to increased susceptibility to apoptosis on the part of these cells (106). These data are reminiscent of events noted in tissue culture, where CD4 clones become more susceptible to apoptosis as they age (107). However, CD8 cell recovery was much more rapid and was not associated with age or thymic enlargement.…”

Section: Thymusmentioning

confidence: 72%

“…Some further supporting data for the concept of decreased apoptosis in aged cells may be found in the report of Lechner et al (345) who found decreased inducibility of CD95 after CD3-stimulation of old persons´ T cells compared to young. However, as already discussed above, susceptibility to AICD of T cell lines established from old donors was greater than those from young donors (345) and culture-aged CD4+ T cell clones show enhanced AICD compared to young cells from the same clone, although they do not express higher levels of CD95 (107). In this respect, therefore, human CD4 and CD8 cells may behave markedly differently, partly explaining the altered CD4:8 ratio seen in the elderly (see section 6).…”

Section: Activation-induced Cell Death and Agingmentioning

confidence: 84%

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T cells and aging update February 1999

Pawelec¹

1999

Front Biosci

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T cell immunosenescence 218effects of dysregulated immune responses in the elderly by supplementation or other approaches may result in an enhancement of their quality of life, and significant reductions in the cost of medical care in old age. FACTORS CONTRIBUTING TO IMMUNO-SENESCENCE HematopoiesisDysregulated hematopoiesis is seen in elderly individuals, raising the possibility that this could contribute to altered immune function in the aged. Hematopoiesis in man may be compromised because of a severely reduced capacity to produce colony stimulating factors (44) and increased production of pro-inflammatory factors such as IL 6 (45), because lower numbers of progenitor cells are present in the BM (46) and because of an age-related decline in proliferative potential of putative haematopoietic stem cells (HSC) (47). In mice, the repopulating potential of murine fetal liver-derived HSC is higher than that of adult BM-derived stem cells (48), suggesting possible aging of the HSC themselves. Normal cells with shorter telomeres possess less remaining replicative capacity than those with longer telomeres (see section 5.2). Accordingly, HSC from adult BM were found to have shorter telomeres than fetal liver-derived or umbilical cord-derived stem cells, consistent with aging of HSC (49). Telomere lengths decreased on culture despite low level expression of telomerase in these cells (50,51), although the rate of basepair loss per population doubling of cells in culture was lower during the first two weeks, when telomerase was upregulated, than in the next two, when it was downregulated (52). The telomerase expressed is therefore functionally active but may not be able to completely maintain telomere length in aging HSC cells. True embryonic stem cells (ESC), on the other hand, which may really be immortal, do retain high levels of telomerase activity (53). On the other hand, ESC from telomerase-knockout mice show gradual telomere shortening over many population doublings (PD) resulting in slowing and eventual cessation of growth (54). Certain animals which do not downregulate telomerase manifest a permanent growth phase and little or no senescence (55,56).

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Section: Activation-induced Cell Death and Agingmentioning

confidence: 69%

Section: Thymusmentioning

confidence: 72%

Section: Activation-induced Cell Death and Agingmentioning

confidence: 84%

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T cells and aging update February 1999

Pawelec¹

1999

Front Biosci

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“…1 Once antigen-specific T-cell clones have been established, they can usually not be expanded beyond another 20 population doublings (PDs). 2,3 Moreover, subcloning of human T lymphocytes is highly inefficient, and subclones that are derived have little replicative potential. This limited life span of human T cells is a drawback for the application of T cells as a source of effector cells in therapeutic settings.…”

Section: Introductionmentioning

confidence: 99%

Ectopic hTERT expression extends the life span of human CD4+ helper and regulatory T-cell clones and confers resistance to oxidative stress–induced apoptosis

Luiten

Pène

Yssel

et al. 2003

Blood

100

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Human somatic cells have a limited life span in vitro. Upon aging and with each cell division, shortening of telomeres occurs, which eventually will lead to cell cycle arrest. Ectopic hTERT expression has been shown to extend the life span of human T cells by preventing this telomere erosion. In the present study, we have shown that ectopic hTERT expression extends the life span of CD4 ؉ T helper type 1 or 2 and regulatory T-cell clones and affected neither the in vitro cytokine production profile nor their specificity for antigen. In mixed cell cultures, ectopic hTERT-expressing clones were found to expand in greater numbers than untransduced cells of the same replicative age. This ectopic hTERT-induced growth advantage was not due to an enhanced cell division rate or number of divisions following T-cell receptor-mediated activation, as determined in carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeling experiments. Moreover, the susceptibility to activation-induced cell death of both cell types was similar. However, cultures of resting hTERT-transduced T cells contained higher frequencies of Bcl-2-expressing cells and lower active caspase-3-expressing cells, compared with wild-type cells. Furthermore, hTERT-transduced cells were more resistant to oxidative stress, which causes preferential DNA damage in telomeres. Taken together, these results show that ectopic hTERT expression not only protects proliferating T cells from replicative senescence but also confers resistance to apoptosis induced by oxidative stress.

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“…During long-term culture, human T cells proliferate for a restricted number of cell divisions, after which the cells cease to proliferate and become senescent. 1 Therefore, in vitro-established antigen-specific CD8 ϩ or CD4 ϩ T clones can usually not be expanded beyond 20 to 30 population doublings, 2,3 and subcloning of established human T-cell clones usually fails or yields subclones with very little replicative potential. The proliferative capacity of T cells may therefore be linked to the replicative history of the cells.…”

Section: Introductionmentioning

confidence: 99%

Telomerase levels control the lifespan of human T lymphocytes

Röth

Yssel

Pène

et al. 2003

Blood

129

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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 (

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Decreased proliferative capacity and increased susceptibility to activation-induced cell death in late-passage human cd4+ tcr2+ cultured T cell clones

Cited by 62 publications

References 29 publications

T cells and aging update February 1999

T cells and aging update February 1999

Ectopic hTERT expression extends the life span of human CD4+ helper and regulatory T-cell clones and confers resistance to oxidative stress–induced apoptosis

Telomerase levels control the lifespan of human T lymphocytes

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