Hedgehog signalling in Cytotoxic T cell function

Cytotoxic T Lymphocytes (CTL) are crucial for our body’s defence against intracellular pathogens and tumours, due to their ability to specifically and very efficiently kill infected and tumourigenic cells. The centrosome plays a critical role in CTL function, docking at the plasma membrane and directing cytotoxic granules for secretion towards the target at the immunological synapse (IS) formed between CTL and target cell. As this docking event is unusual, but also occurs during primary cilium formation, we wanted to address how it is regulated. We found that Hh signalling has an important role in CTL killing. T cell receptor (TCR) activation, which pre-arms CTL with cytotoxic granules, also initiated Hh signalling. These events “pre-armed” CTL for the actin remodelling required for centrosome polarisation and granule release.  Inhibition of Hh signalling either genetically or with small molecule inhibitors led to diminished CTL killing. In contrast, CTL from patients with Gorlin syndrome, which have hyperactive Hh signalling due to a mutation of the negative pathway regulator PTCH1, had greatly increased killing capacity compared to CTL from healthy donor controls. This suggests that Hh inhibitors — currently in the clinic and in trials as treatment for various cancers — diminish the immune systems’ very own anti-tumour response.
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Dr Klaus Okkenhaug
The Brian Heap Seminar Room