Gillian Griffiths, FRS

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.

CTLs form a highly dynamic immune synapse with their targets and killing is accomplished in minutes. One reason that CTLs are so effective is because they are serial killers, killing one target after another.

Using a combination of genetics, transcriptomics, biochemistry and high-resolution microscopy our research has shown how organelles including the centrosome, specialized secretory lysosomes, mitochondria and dynamic membrane changes are coordinated in response to signal strength. We have made important conceptual advances, revealing parallels between the immune synapse and cilia, demonstrating roles for common molecular pathways including Hedgehog signaling and membrane specialization. Using scRNAseq we showed that T cell receptor (TCR) signal strength controls how rapidly and simultaneously naïve T cells initiate activation, demonstrating how finite signaling machinery can further extend the range of responses generated in an immune response. We also uncovered a novel role for mitochondrial translation in controlling sustained, serial killing.

More recently we showed that activated TCRs are shed by ectocytosis (outward budding) at the immune synapse rather than endocytosis (internalization) as previously thought. Ectocytosis simultaneously removes activated TCRs and initiates cell separation, seamlessly linking TCR activation with down-regulation and CTL release. Our findings suggest a model of ectosome formation that is likely to apply to many other biological systems in which outward budding vesicles are generated during receptor signaling.

Our current research is focused on using multispectral and high-resolution imaging to follow the rapid reorganization of intracellular organelles, identifying polarity cues and identifying the molecular drivers of ectocytosis. We also use chimeric antigen receptor (CAR) T cells to ask why these cells are less effective killers than native CTLs and how the underlying cell biology differs.