The in vitro senescence of human T lymphocytes: Failure to divide is not associated with a loss of cytolytic activity or memory T cell phenotype

Perillo, Nancy L.; Naeim, Faramarz; Walford, Roy L.; Effros, Rita B.

doi:10.1016/0047-6374(93)90121-7

Cited by 63 publications

(35 citation statements)

References 36 publications

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“…The proportion of cells expressing c-myc (G0 to G1 marker) and c-myb (G1 to S marker) was decreased after PHA stimulation of old T cells, but the amount per cell seemed to remain the same as in young T cells (178). T cells retaining antigen recognition and effector function, yet apparently in a post-mitotic senescent or presenescent state have been described (179). These investigators also demonstrated that aged human T cells paralleled the senescent phenotype of fibroblasts in that on restimulation, fewer cells responded by entering the cell cycle, the remainder being arrested before S-phase.…”

Section: T Cell Receptor Signal Transductionmentioning

confidence: 99%

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: T Cell Receptor Signal Transductionmentioning

confidence: 99%

T cells and aging update February 1999

Pawelec¹

1999

Front Biosci

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“…Senescent T lymphocytes fail to proliferate in response to renewed attempts at stimulation, which frequently lead to massive cell death by apoptosis (2), but they can be maintained in culture for a long time, usually several months, if fresh IL-2 is added periodically. Senescent T cells are able to upregulate IL-2R␣ surface expression in response to Ag stimulation (3). Expression of other surface markers is generally unchanged, with a few exceptions, notably the decline in levels of the costimulatory receptor CD28 (4 -6).…”

mentioning

confidence: 94%

“…Expression of other surface markers is generally unchanged, with a few exceptions, notably the decline in levels of the costimulatory receptor CD28 (4 -6). Senescent CD4 ϩ T cells are still able to secrete a number of cytokines when stimulated (5), and senescent CD8 ϩ T cells retain high levels of Ag-specific cytotoxicity (3).…”

mentioning

confidence: 99%

“…Expression of the enzyme telomerase allows germline cells and tumor cells to maintain telomere length during proliferation. Ectopic expression of human telomerase catalytic subunit (hTERT) 3 is sufficient to permit some cell types, such as fibroblasts, retinal pigment epithelial cells, and endothelial cells (7,8), to avoid senescence and to proliferate indefinitely. These immortalized cells continue to display normal cellular functions and do not undergo changes characteristic of malignant transformation (9,10).…”

mentioning

confidence: 99%

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Ectopic Human Telomerase Catalytic Subunit Expression Maintains Telomere Length But Is Not Sufficient for CD8+ T Lymphocyte Immortalization

Migliaccio

Amacker²,

Just³

et al. 2000

The Journal of Immunology

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Like most somatic human cells, T lymphocytes have a limited replicative life span. This phenomenon, called senescence, presents a serious barrier to clinical applications that require large numbers of Ag-specific T cells such as adoptive transfer therapy. Ectopic expression of hTERT, the human catalytic subunit of the enzyme telomerase, permits fibroblasts and endothelial cells to avoid senescence and to become immortal. In an attempt to immortalize normal human CD8+ T lymphocytes, we infected bulk cultures or clones of these cells with a retrovirus transducing an hTERT cDNA clone. More than 90% of transduced cells expressed the transgene, and the cell populations contained high levels of telomerase activity. Measuring the content of total telomere repeats in individual cells (by flowFISH) we found that ectopic hTERT expression reversed the gradual loss of telomeric DNA observed in control populations during long term culture. Telomere length in transduced cells reached the levels observed in freshly isolated normal CD8+ lymphocytes. Nevertheless, all hTERT-transduced populations stopped to divide at the same time as nontransduced or vector-transduced control cells. When kept in IL-2 the arrested cells remained alive. Our results indicate that hTERT may be required but is not sufficient to immortalize human T lymphocytes.

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“…S1). The cell population could be maintained in culture for several weeks with appropriate culture conditions (IL-2 stimulation and fresh media), suggesting the state of replicative senescence had been reached (33). At different stages in culture, cells were sampled in order to observe changes in cell morphology, cycle, phenotypical markers and signaling as they "aged" in culture (supplemental Fig.…”

Section: Global Characteristics Of Age-associated Protein Expression mentioning

confidence: 99%

Predicting Cytotoxic T-cell Age from Multivariate Analysis of Static and Dynamic Biomarkers

Rivet

Hill

et al. 2011

Molecular & Cellular Proteomics

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Adoptive T-cell transfer therapy relies upon in vitro expansion of autologous cytotoxic T cells that are capable of tumor recognition. The success of this cell-based therapy depends on the specificity and responsiveness of the T cell clones before transfer. During ex vivo expansion, CD8؉ T cells present signs of replicative senescence and loss of function. The transfer of nonresponsive senescent T cells is a major bottleneck for the success of adoptive T-cell transfer therapy. Quantitative methods for assessing cellular age and responsiveness will facilitate the development of appropriate cell expansion and selection protocols. Although several biomarkers of lymphocyte senescence have been identified, these proteins in isolation are not sufficient to determine the age-dependent responsiveness of T cells. We have developed a multivariate model capable of extracting combinations of markers that are the most informative to predict cellular age. To acquire signaling information with high temporal resolution, we designed a microfluidic chip enabling parallel lysis and fixation of stimulated cell samples on-chip. The acquisition of 25 static biomarkers and 48 dynamic signaling measurements at different days in culture, integrating single-cell and population based information, allowed the multivariate regression model to accurately predict CD8؉ T-cell age. From surface marker expression and early phosphorylation events following T-cell receptor stimulation, the model successfully predicts days in culture and number of population doublings with R 2 ‫؍‬ 0.91 and 0.98, respectively. Furthermore, we found that impairment of early signaling events following T cell receptor stimulation because of long term culture allows prediction of costimulatory molecules CD28 and CD27 expression levels and the number of population divisions in culture from a limited subset of signaling proteins. The multivariate analysis highlights the information content of both averaged biomarker values and heterogeneity metrics for prediction of cellular age within a T cell population.

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The in vitro senescence of human T lymphocytes: Failure to divide is not associated with a loss of cytolytic activity or memory T cell phenotype

Cited by 63 publications

References 36 publications

T cells and aging update February 1999

T cells and aging update February 1999

Ectopic Human Telomerase Catalytic Subunit Expression Maintains Telomere Length But Is Not Sufficient for CD8+ T Lymphocyte Immortalization

Predicting Cytotoxic T-cell Age from Multivariate Analysis of Static and Dynamic Biomarkers

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