Role of Telomere and telomerase In Human Lymphocyte Function and Aging

National Institute On Aging

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Abstract

Age-associated increases in antinuclear antibodies (ANA) in the general population are commonly noted but the mechanisms underlying this observation are unclear. This study aims to evaluate whether shorter peripheral blood mononuclear cell (PBMC) telomere length, a marker of more advanced biological age, is associated with ANA positivity prevalence and incidence in middle and older aged autoimmune disease-free individuals from the Baltimore Longitudinal Study of Aging (BLSA). Telomere length was measured by Southern Blot and categorized into tertiles. ANA was measured in a 1:80 and a 1:160 dilution of sera by immunofluorescence using HEp-2 cells (seropositive = 3 or 4). Multiple logistic regression was used to estimate the odds ratios and 95% confidence intervals of ANA positivity comparing the shorter tertiles of telomere length to the longest tertile for two cross-sectional points in time and then longitudinally to assess the association between shorter telomere length and incident ANA positivity. Cross-sectional analyses were adjusted for sex, race and BMI (N = 368 baseline, N = 370 follow-up) and longitudinal analyses were adjusted for sex, race, BMI and time between baseline and follow-up (N = 246). No statistically significant cross-sectional associations were observed at baseline or follow-up. Among those where ANA negative at baseline, individuals with shorter telomeres were more likely to be ANA positive at follow-up, an average 13 years later. Individuals with short telomeres at both time periods were more likely to be ANA positive. Findings suggest that ANA positivity in the general population may be indicative of immune dysfunction resulting from advanced cellular aging processes. Stimulation of human primary T cells with immobilized anti-CD3 and CD28 antibodies in vitro provide a system to study T cell activation and proliferation and an avenue for expanding T cells for immunotherapy. Magnetic beads conjugated with anti-CD3 and CD28 antibodies (D-TCA) have been a golden standard for stimulating human primary T cells in vitro. Here, we report that an application using anti-CD3 and anti-CD28 antibodies conjugated on lipid microbubbles (MB-TCA) to stimulate primary human nave T cells resulted in expansion superior to D-TCA. In 56-day cultures with three repeated stimulation cycles (14 days per stimulation), we found that 1) MB-TCA induced significantly better expansion (20 and 10-fold increase) of nave CD4+ and CD8+ T cells than did D-TCA; 2) MB-TCA and D-TCA stimulated T cells had a similar number of initial cell divisions but MB-TCA had significantly lower activation-induced cell death than D-TCA; 3) MB-TCA induced higher telomerase activity and lower telomere length loss than did D-TCR; and 4) MB-TCA stimulated T cells produced less TNF than did D-TCA and blocking TNF action via adding an antibody against TNF receptor (TNFRSF1A) significantly improved expansion of T cells activated by D-TCA in vitro. Together, we demonstrated that the MB-TCA induces a better expansion of human nave T cells in vitro and offers advantages in both basic and clinical applications in which the outcome depends on the number of T cells.