Dynamic changes at the immune synapse controlling CTL function (360G-Wellcome-306545_Z_23_Z)

Cytotoxic T lymphocytes (CTLs) are vital to human health and immunity, using highly sensitive T cell receptor (TCR) recognition and polarised secretion of cytolytic proteins to destroy virally infected and cancer cells. The effectiveness of CTLs is greatly enhanced by the fact that they are serial killers, able to kill one target after another. Their potency is proving successful in immunotherapies employing Chimeric Antigen Receptors (CARs) that recognise cancer cells. However, CARs are less sensitive and elicit less effective killing than TCRs. Why, is poorly understood. This proposal aims to understand how dynamic changes across the immune synapse, formed as CTL encounter target cells, control CTL function. How and why multiple organelles polarise tightly within the synapse and what their roles are is not fully understood. Using CRISPR screening, functional read-outs and high-resolution live cell imaging we will not only identify new pathways but will determine when and where they act, establish the molecular mechanisms involved, and show how they are linked to TCR signalling. These findings will transform our understanding of how CTL function is controlled. Moreover, they will enable us to discover why CARs are unable to elicit more efficient killing and provide the foundation for improving immunotherapies.