Regulation and function of telomerase in T cells

National Institute On Aging

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Abstract

Telomerase activity is tightly regulated during T cell development, differentiation, and activation. In human peripheral blood resting T cells, telomerase activity is low to undetectable despite telomerase reverse transcriptase (TERT) is detected. Alternate splicing of TERT is found in activated T cells, but it is unclear whether the full-length and alternative splicing of TERT exists in every T cell or different T cell contains different forms of TERT. It is also unclear whether lack of telomerase activity in resting T cells is a result of non-functional splicing products (ASP) of TERT mRNA and/or missing proper post-translational modifications of TERT protein. To address these questions, we applied single cell RT-PCR method for analyzing TERT full-length and ASP in freshly isolated resting and in vitro activated T cells. We found that 1) 39% of the resting T cells expressed only full-length TERT, 34% expressed both full-length and ASP, and 27% expressed only TERT ASP; and 2) in vitro activation led to the loss of expressing only full-length TERT cells and an increase of only TERT ASP cells. Intriguingly, the level of telomerase activity increased significantly from resting to activated T cells despite of higher percentage of activated T cells containing TERT ASP. Currently, we are studying the relationship of TERT mRNA (full-length and ASP) and telomerase activity. Telomere shortens in peripheral lymphocytes with age. But it is unknown whether telomerase activity decreases in lymphocytes with age as well. We have followed 200 BLSA participants over an average 5 year time span. We found that telomerase activity declined with age in resting and in vitro activated T cells. Interestingly, we found that telomerase activity declined also in the resting but not in vitro activated B cells. Currently we are testing different in vitro stimulation conditions to determine if the difference of this age-associated decline of telomerase activity between T and B cells is intrinsic or extrinsic (stimulation conditions).