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A comprehensive comparison of signalling used in the accessing and regulation of cytolysis in cytotoxic T lymphocytes and natural killer cells

Rachel Ambler

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Cytotoxic T cells (CTLs) and natural killer (NK) cells are essential defensiveimmune components which eliminate infected, damaged and tumourigenic cells. Both release cytotoxic granules in a highly specific manner to deliver a lethal hit to a single cell. Despite their functional similarities, different receptor repertoires mean the signalling pathways used by these cells to access and regulate cytolysis may be significantly different. Currently, a direct and comprehensive comparison of signalling in CTLs versus NK cells has never been performed, partly due to a lack of quantitative data regarding the highly complex signalling pathways occurring at the lytic synapse after targetcell recognition. Here we propose to utilise high resolution imaging protocolsdeveloped by the Wuelfing lab to generate an expansive data set on the spatiotemporal distribution patterns of signalling molecules at the lytic synapse1. Combined with biochemical studies and RNAi experiments, this approach will allow the construction of quantitative models describing key elements of cytolytic effector signalling in relation to function. Key differences in the signalling mechanisms used by CTLs and NK cells will also become apparent. We predict the unprecedented level of comprehension obtained by this study will contribute greatly to the field of cytolysis and therapeutic development.

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