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Cell death and longevity: implications of Fas-mediated apoptosis in T-cell senescence
J D Mountz1, J Wu, T Zhou
1Department of Medicine, University of Alabama at Birmingham 35294-0007, USA. John.Mountz@ccc.uab.edu
Abstract:
Two prominent features of immune senescence are altered T-cell phenotype and reduced T-cell response. We have previously shown that T-cell senescence is greatly reduced in CD2-fas transgenic mice, in which the Fas apoptosis molecule is constantly expressed on T cells. Using a different experimental approach, the relationship between T-cell senescence and apoptosis was analyzed on human peripheral blood mononuclear cells. The results indicate that there was increased apoptosis of CD45RO- (CD45RA+) T cells upon activation. We propose that this could account for the increase in CD45RO+ "memory" T cells with aging in humans. T-cell responsiveness remained high in CD2-fas transgenic aged mice, but there was no increase in overall life span of these mice. Increased T-cell responsiveness was associated with an increased acute-phase response and serum amyloid A deposition in the glomerulus of aged CD2-fas transgenic mice. Therefore, restoration of the T-cell immune function using a CD2-fas transgene produced undesirable side-effects to aged transgenic mice. In addition to its role in activation-induced cell death, Fas-mediated apoptosis may be important in deleting T cells in response to DNA damage. It may also inhibit cell-cycle progression by cleaving various kinases and DNA repair enzymes. We observed that cell lines derived from human premature aging diseases have a higher sensitivity to Fas-mediated apoptosis. The implications of these observations are discussed.
Insights
Immune senescence involves T-cell changes. Enhancing Fas-mediated apoptosis in T cells reduced senescence but caused harmful side effects in aged mice, suggesting complex roles in aging.
Area of Science:
- Immunology
- Cell Biology
- Aging Research
Background:
- Immune senescence is characterized by altered T-cell phenotype and reduced responsiveness.
- Fas apoptosis molecule plays a role in T-cell death and immune regulation.
- Previous studies showed reduced T-cell senescence in CD2-fas transgenic mice.
Purpose of the Study:
- To analyze the relationship between T-cell senescence and apoptosis in human cells.
- To investigate the effects of enhanced Fas-mediated apoptosis on T-cell populations and aging.
- To explore the potential side effects of restoring T-cell immune function in aged individuals.
Main Methods:
- Analysis of human peripheral blood mononuclear cells.
- Experimental approach using CD2-fas transgenic mice with constitutive Fas expression on T cells.
- Observation of cell lines from human premature aging diseases.
Main Results:
- Increased apoptosis of CD45RO- (CD45RA+) T cells upon activation in human cells.
- T-cell responsiveness remained high in aged CD2-fas transgenic mice, but lifespan did not increase.
- Enhanced T-cell responsiveness was linked to increased acute-phase response and kidney damage in transgenic mice.
- Cell lines from premature aging diseases showed higher sensitivity to Fas-mediated apoptosis.
Conclusions:
- Increased T-cell apoptosis upon activation may explain the rise in memory T cells with human aging.
- Restoring T-cell immune function via CD2-fas transgene leads to detrimental side effects in aged mice.
- Fas-mediated apoptosis is crucial for T-cell deletion in response to DNA damage and may inhibit cell cycle progression.