Telomerase is a ribonucleoprotein enzyme that catalyzes telomere synthesis and other non-telomere lengthening activity. Telomerase consists of two core components: telomerase reverse transcriptase (TERT) and telomerase RNA template (TERC). TERT serves as a rate-limiting factor whereas TERC is present ubiquitously. Telomerase activity is tightly regulated during T cell development, differentiation, and activation. Human blood T cells have low or undetectable level of telomerase activity whereas express the limiting the component of telomerase, telomerase reverse transcriptase (TERT). Alternate splicing of TERT (ASP) is found in activated T cells and is associated loss of telomerase function. However, 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 ASP of TERT mRNA. To address these questions, we applied single cell RT-PCR method for analyzing full-length and ASP of TERT in freshly isolated resting and in vitro activated T cells. We found that 73% of the resting T cells express full-length TERT, approximately half of them also express ASP, and 27% express only ASP;and reduction of full-length of TERT and increase of ASP were observed after in vitro activation despite an increase of telomerase activity from resting to activated T cells. Currently, we are studying the role of TERT ASP in regulation of telomerase activity and differentiation in T cells. Our previous study showed that telomerase is involved in IL-7 mediated differential survival of human nave and memory CD4+ T cells. However, the mechanism underlying telomerase (TERT) mediated T cell survival is not known. To elucidate the mechanism of TERT in T cell survival, we investigated the role TERT in activation and homeostatic cytokine mediated survival of T cells (both CD4 and CD8) using mouse model that are deficient of TERT or TERC. Our preliminary data showed that T cells lack of TERT have increased cell death. The current focus is to identify the factors that are associated with TERT in regulation of T cell survival and death. Telomere shortens in peripheral lymphocytes with age but it is unknown whether telomerase activity decreases in lymphocytes with age. We have followed 220 BLSA participants over an average 5-year time span and compared telomerase activity in resting and activated B and T cells. We found that telomerase activity declined with age in resting and in vitro activated T cells, and that a significant correlation between telomere length and telomerase activity in resting T cells. In addition, we found that telomerase activity declined also in the resting B cells 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) and also extended to 10-year time span.
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