Abstract

Cytotoxic T Lymphocytes (CTL) are an important part of the adaptive immune system and can kill virally infected and tumorigenic cells. The centrosome plays a critical role in CTL function, docking at the plasma membrane and directing cytotoxic granules for secretion at the immunological synapse (IS). Centrosome docking at the plasma membrane is very unusual but also occurs during cilia formation. The primary cilium, formed by virtually all cells, is essential for vertebrate Hedgehog (Hh) signalling. Lymphocytes do not form primary cilia, but here we found that Hh signalling played an important role in CTL killing. T cell receptor (TCR) activation, which pre-arms CTL with cytotoxic granules, also initiated Hh signalling. Hh pathway activation occurred intracellularly and triggered Rac1 synthesis. 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 , have greatly increased killing capacity compared to CTL from healthy donor controls.