Control of secretion at the immunological synapse
Cytotoxic T lymphocytes (CTLs) play a critical role in the immune system, recognizing and destroying virally infected cells and cancer targets with remarkable specificity. These cells are extraordinarily efficient serial killers that rapidly deliver their lethal hit using precisely polarized secretion of cytolytic proteins from modified lysosomes to destroy their targets. CTLs provide a fascinating system in which to understand the cell biology of secretion in a specialized cell type. This is particularly important right now, with new immunotherapies focused on harnessing the cytotoxic potential of these cells to combat cancer.
The ability to grow primary CTLs in culture from <5ml of blood has been very powerful, allowing us early on to use genetics to understand function by generating CTLs from patients with genetic mutations. Using biochemical, molecular and high-resolution imaging approaches we have made many fundamental discoveries both in the field of cytotoxicity as well as cell biology, identifying proteins required to make a lysosome a secretory organelle and describing a novel role for the centrosome in CTL secretion revealing unexpected parallels with ciliogenesis.
Our high resolution, temporal imaging has pinpointed the timing and location of key events leading to secretion with increasing detail emerging with each new probe examined. With the ability to express tagged or modified proteins in CTLs together with CRISPR technology to generate mutations by design, it is now possible to probe CTL function in greater detail than ever before.
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