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Title: The role of metabolism during T cell senescence
Author: Callender, Lauren Amy
ISNI:       0000 0004 9355 3543
Awarding Body: Queen Mary University of London
Current Institution: Queen Mary, University of London
Date of Award: 2020
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The impact of T cell senescence during ageing is well established. However, T cell senescence is now recognised to play a role in a variety of age-related and metabolic diseases, such as rheumatoid arthritis and cardiovascular disease. It is therefore crucial to gain a better understanding of the mechanisms that control T cell senescence. The loss of mitochondria has been linked to both cellular senescence and ageing; however, it is still unclear whether mitochondria play a causal role in T cell senescence. Data presented here provides evidence that the differing susceptibilities to senescence that exist between CD8+ and CD4+ T cells is due to the inherent differences in mitochondrial content and cellular metabolism. Notably CD4+ T cells displayed a higher mitochondrial mass, shown to be the result of a GATA3-PGC1a complex, which is recruited as a consequence of DNA damage. Additionally, this thesis demonstrates the existence of a novel naïve-like senescent T cell subset, highlighting the heterogeneity of senescent T cells. This subset was found to arise because of inflammation; therefore, senescent T cells isolated from people living with type 2 diabetes (T2D) were used as a model to examine the characteristics of this subset further. Inflammatory-derived senescent T cells were phenotypically distinct to those examined from healthy age-matched control donors. With T2D senescent T cells expressing fewer of the traditional senescent-associated T cell markers and retaining more proliferative capacity, indicating they were derived from a less differentiated T cell subset. Despite this, inflammatory-derived senescent T 4 cells exhibited more severe mitochondrial dysfunction and dysregulated nutrient uptake and usage. Collectively, this thesis highlights the heterogeneity of senescent T cells and supports the ever-growing appreciation that cellular metabolism and senescence are intimately linked. Going forward, mitochondrial health and cellular metabolism should be included to better define the senescence phenotype.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available