Role of Telomere and telomerase In Human Lymphocyte Function and Aging

免疫衰老的一些特征已经被确定，但根本原因尚未完全了解。我们通过纵向分析465例首次就诊时年龄从21岁到88岁的受试者，平均随访13年（7-19年），分析了免疫系统衰老的三个参数（端粒长度、炎症细胞因子和CMV抗体滴度）。观察到pbmc端粒长度的变化率变化很大，端粒缩短的平均速度相对较慢（-16 bp/年）。同样，体内三种炎症相关细胞因子（IFN-、IL-6和IL-10）和抗巨细胞病毒IgG滴度也随着年龄的增长而显著增加，这在个体之间也有很大差异。尽管不同炎症因子之间存在正相关变化，但我们未观察到端粒长度、炎症因子和抗巨细胞病毒IgG滴度的变化率之间存在显著相关性，这表明端粒磨损、循环炎症因子升高和抗巨细胞病毒IgG滴度的年龄相关轨迹是独立的。免疫老化过程复杂且因人而异，使用多种生物标志物对评估免疫系统的生物老化至关重要。

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.