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Aging leads to disturbed homeostasis of memory phenotype CD8(+) cells
Xiaohong Zhang1, Hideki Fujii, Hidehiro Kishimoto
1Department of Immunology, IMM4 The Scripps Research Institute, La Jolla, CA 92037, USA.
Insights
Aging significantly reduces T cell turnover in older mice, particularly in memory CD8(+) T cells. This decline is linked to increased Bcl-2 expression and type I interferons, suggesting impaired immune responses in aged individuals.
Area of Science:
- Immunology
- Aging Research
- Cellular Biology
Background:
- T cell turnover, crucial for immune homeostasis, declines with age.
- Memory-phenotype CD8(+) T cells play a vital role in adaptive immunity.
- Age-related changes in the immune system can lead to impaired responses.
Purpose of the Study:
- To investigate the mechanisms behind reduced T cell turnover in aged mice.
- To determine the role of the host environment and specific molecular factors in age-related T cell dysfunction.
- To explore potential therapeutic targets for restoring T cell function in aging.
Main Methods:
- Adoptive transfer experiments to assess T cell behavior in young and aged hosts.
- Analysis of T cell proliferation and response to cytokines like IL-15 in vivo and in vitro.
- Measurement of Bcl-2 expression and type I interferon (IFN-I) levels in T cells and serum.
Main Results:
- Aged mice exhibited significantly reduced turnover of memory-phenotype CD8(+) T cells compared to young mice.
- Reduced turnover was attributed to an inhibitory aged host environment.
- Increased Bcl-2 expression and elevated serum IFN-I levels in aged T cells were identified as key inhibitory factors.
- In vitro studies showed aged T cells responded well to IL-15, suggesting impaired in vivo signaling.
Conclusions:
- Reduced T cell turnover in aging is multifactorial, involving increased Bcl-2 expression and high IFN-I levels.
- These factors collectively inhibit T cell proliferation and responsiveness in aged individuals.
- Targeting Bcl-2 and IFN-I pathways may offer strategies to rejuvenate T cell function in aging populations.
Abstract:
Examining the rate of in vivo T cell turnover (proliferation) in aged mice revealed a marked reduction in turnover at the level of memory-phenotype CD44(hi) CD8(+) cells relative to young mice. Based on adoptive transfer experiments, the reduced turnover of aged CD44(hi) CD8(+) cells reflected an inhibitory influence of the aged host environment. Aged CD44(hi) CD8(+) cells also showed poor in vivo responses to IL-15 and IL-15-inducing agents, but responded well to IL-15 in vitro. Two mechanisms could account for the reduced turnover of aged CD44(hi) CD8(+) cells in vivo. First, aging was associated with a prominent and selective increase in Bcl-2 expression in CD44(hi) CD8(+) cells. Hence, the reduced turnover of aged CD44(hi) CD8(+) cells may in part reflect the antiproliferative effect of enhanced Bcl-2 expression. Second, the impaired in vivo response of aged CD44(hi) CD8(+) cells to IL-15 correlated with increased serum levels of type I interferons (IFN-I) and was largely reversed by injection of anti-IFN-I antibody. Hence the selective reduction in the turnover of aged CD44(hi) CD8(+) cells in vivo may reflect the combined inhibitory effects of enhanced Bcl-2 expression and high IFN-I levels.