Role of Telomere and telomerase In Human Lymphocyte Function and Aging

National Institute On Aging

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Abstract

Telomere length records past cell divisions and predicts cellular replicative potential. The underlying mechanisms of short telomere-induced cell senescence are largely supported by cultured cells and genetically modified mouse models. The cell cycle is a tightly controlled process, with CDKN2a (p16) and CDKN1a (p21) being key regulators of cell cycle progression. Their expressions significantly increase in human T cells with age. However, it is not fully known whether telomere length changes similarly or differently across various types of blood cells, how shorter telomeres in T cells trigger the cessation of the cell cycle, or what regulates p16 or p21 expressions in T cells with shorter telomeres. The lack of functional measurements of short telomere lymphocytes impedes precise interpretation of the roles of telomeres, p16, and p21 in T cells. We conducted a longitudinal study of the Baltimore cohort from the Epidemiologic Catchment Area study (n=307, aged 41 to 93 years) by investigating telomere length dynamics across five major blood immune cell types: B cells, CD4+ T cells, CD8+ T cells, natural killer (NK) cells, and monocytes. Utilizing our recently developed FlowFISH method, which enables simultaneous measurement of telomere length in five cell types, we analyzed frozen PBMCs. We employed five heat-resistant, fluorescently labeled antibodies (CD19, CD4, CD8, CD56, and CD14) and collected data using BD-Discovery S8 spectral flow cytometer. A control PBMC with known telomere length was used to convert fluorescence intensity to actual kilobases. Applying a mixed-effects linear regression model to assess age-related telomere length changes, we observed distinct rates of telomere attrition among the different immune cell types. CD8+ T cells exhibited the fastest telomere attrition (-57 bp/year), followed by CD4+ T cells (-46 bp/year), NK cells (-29 bp/year), B cells (-18 bp/year), and monocytes (-17 bp/year). Interestingly, lymphocytes, which express telomerase, showed faster attrition compared to monocytes, which do not express telomerase (83-85). This may be attributed to the longer lifespan and higher proliferation rate of lymphocytes compared to monocytes. These findings highlight clear differences in telomere attrition rates among various immune cell types with age; however, the underlying regulatory mechanisms remain elucidated. To explore the relationship between telomere length (TL) dynamics and age across various immune cell subsets, we calculated Pearson's correlation coefficients. Our analysis revealed strong positive correlations in both TL and rates of telomere attrition among four lymphocyte subsets: CD4⁺ T cells, CD8⁺ T cells, B cells, and natural killer (NK) cells. Notably, the proportion of naïve CD8⁺ T cells showed a positive correlation with TL across these lymphocyte subsets, whereas the percentage of CD8⁺ terminal effector memory cells re-expressing CD45RA (EMRA) exhibited a negative correlation with TL. These findings suggest that the composition of immune cell subsets, characterized by distinct TLs, contributes to the overall TL dynamics observed in lymphocytes. The positive correlation between naïve CD8⁺ T cells and TL aligns with existing literature indicating that naïve T cells possess longer telomeres compared to their differentiated counterparts (86). Conversely, the negative correlation between CD8⁺ EMRA cells and TL is consistent with findings that EMRA subsets, defined as CD45RA⁺CCR7⁻CD28⁻ T cells, have the shortest telomeres among T-cell subsets and exhibit low proliferative capacity. Our findings reveal that: 1) Distinct telomere attrition rates of five major immune cell types. Further understanding the mechanisms underlying these differences warrants further investigation, and 2) Significant positive correlations exist among the telomere lengths and attrition rates of the four lymphocyte subsets examined. Notably, the proportion of naïve CD8+ T cells is positively correlated with telomere lengths across these lymphocyte types, whereas the percentage of CD8+ EMRA subset shows a negative correlation. These findings suggest that the composition of immune cell subsets, characterized by varying telomere lengths, contributes to the overall telomere dynamics within the lymphocyte population.