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Title: Molecular tuning of telomerase activity in senescent human T cells
Author: Lanna, A.
ISNI:       0000 0004 8503 5885
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2016
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Telomerase, a RNA-dependent DNA polymerase that adds telomeric DNA at the ends of eukaryotic chromosomes, is essential for the lifelong preservation of the proliferative potential of antigen specific T lymphocytes. However, senescent T cells that have low telomerase activity, short telomeres and lack of replicative capacity accumulate in old humans, patients with chronic viral infections and cancer. The mechanisms inhibiting telomerase in these cells are poorly understood. Here I investigated the molecular pathways causing telomerase dysfunction and defined an unrecognized mode of p38 MAPK activation in T cells. To identify mechanisms involved in telomerase down-regulation, I activated T cells in the presence of IFN-α, an inflammatory cytokine that inhibits telomerase. Telomerase down-regulation was mediated in part by p38 activation. I further investigated the upstream regulatory network of p38 MAPK in senescent T cells. Unexpectedly, spontaneous p38 activation in these cells was not regulated by either the 'canonical' MAPK cascade or the 'alternative' pathway downstream of the T cell receptor, in contrast to the current paradigm of how this pathway is activated in T cells. Instead, the senescence-related DNA damage response pathway activates the low nutrient sensor AMPK, which in turn induces p38 auto-phosphorylation through the scaffold molecule TAB1. These findings establish a third, 'intrasensory' pathway for p38 activation in T cells in which low nutrient and genotoxic signalling converge to inhibit proliferative responses. This can be reversed by blocking AMPK/TAB1 mediated activation of p38, which may represent a selective way for boosting T cell activity during ageing.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available