Role of Telomere and telomerase In Human Lymphocyte Function and Aging

National Institute On Aging

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Abstract

A number of hallmarks of immune aging have been identified but underpinning causes are not fully understood. We analyzed three parameters (telomere length, inflammatory cytokines, and antibody titer to CMV) of immune system aging through a longitudinal analysis of 465 subjects ranging in age from 21 to 88 at the first visit, with an average of 13 years (7-19 years) follow-up. A highly variable rate of change in telomere length of PBMCs with a relatively slow average rate of telomere shortening (-16 bp/year) was observed. Similarly, there were significant increases with age in vivo in three inflammatory-related cytokines (IFN-, IL-6 and IL-10) and in anti-CMV IgG titer, which varied widely across individuals as well. Although there were positive correlative changes among different inflammatory cytokines, we did not observe significant correlations among the rate of changes in telomere length, inflammatory cytokines, and anti-CMV IgG titers, indicating age-related trajectories of telomere attrition, elevated circulating inflammatory cytokines, and anti-CMV IgG are independent. Immune aging processes are complex and vary across individuals, and the use of multiple biomarkers is essential to evaluation of biological aging of the immune system. To understand the role of telomerase in T cell differentiation and function, we analyzed human telomerase reverse transcriptase (hTERT) mRNA expression and telomerase activity in six T cell subsets from 85 healthy human donors (aged 17-82 years old). We found that levels of hTERT mRNA and telomerase activity were higher in CD4 T cell subsets as compared to corresponding CD8 T cell subsets and decreased from nave (TN) to memory (central, TCM and effector, TEM). In all six subsets, in vitro activation with anti-CD3/CD28 antibody led to increased amounts of hTERT mRNA as well as telomerase enzymatic activity, while the differences in hTERT amounts and telomerase activity among subsets remained in the same order observed prior to stimulation. Next, we compared activation-induced proliferation in vitro over the course of a 15-day culture and found that expansion and survival were most robust in CD4 TN and poorest in CD8 TEM, correlating with their respective levels of hTERT mRNA and telomerase activity. Finally, we tested directly of the role of telomerase in T cell proliferation by knock-down hTERT mRNA by an anti-sense DNA oligo of hTERT. We found that knock-down hTERT in CD4 TN cells reduced hTERT mRNA, telomerase activity and cell proliferation in response to anti-CD3 and anti-CD28 stimulation. These findings suggest that greater hTERT expression and telomerase activity promote T cell proliferative potential, and that differentiation is associated with a loss of proliferative potential in T cells.