mTOR-independent regulation of senescent human CD8+ T cells

Ageing is accompanied by alterations to T cell immunity and also by a low-grade chronic inflammatory state termed inflammageing. The significance of these phenomena is highlighted by baseline inflammation being a predictor of earlier mortality. As T cells age they lose proliferative capacity but they secrete high levels of pro-inflammatory cytokines and show potent cytotoxic activity. The maintenance of an inflammatory state is an energy-intensive process involving a switch from resting metabolic requirements to a highly active state which enables the production of host defence factors. How T cells derive their energy is now being clarified, however it is not known how senescent human T cells generate the energy required for their functional activity nor the metabolic checkpoints that regulate T cell senescence.
A key metabolic regulator is mTOR, which controls cell growth and metabolism in response to nutrients, growth factors and cellular energy and it is considered widely that the inhibition of mTOR may be a potential target for retarding the effects of ageing. However I have shown that senescent T cells are unable to phosphorylate mTOR suggesting that the canonical mTOR pathway does not play a role in senescent T cells. Instead senescent cells utilise the p38 MAPK pathway to regulate autophagy through the regulation of Atg9-p38IP interactions.


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Dr Michelle Linterman
The Brian Heap Seminar Room