Determining the role of Hedgehog signalling in the development and function of Natural Killer cells

Natural killer (NK) cells are innate immune cells with a crucial role in anti-viral and anti-
tumour immunity. NK cells develop in the bone marrow before maturing into cytotoxic effector
cells peripherally. Specific NK cell killing is achieved through expression of a number of
germline-encoded receptors. Following receptor ligation, NK cells form an immunological
synapse (IS) with target cells to allow polarised secretion of cytotoxic granules whilst
minimising bystander killing. Recently, NK cells became attractive as cancer immunotherapy
targets due to their capacity to lyse cancer cells without prior sensitisation.
Despite thorough characterisation of NK cell receptor signalling pathways, intracellular
pathways are less well understood. The hedgehog (Hh) signalling pathway is known to have
an important role during embryogenesis and adult tissue maintenance. Hh signalling has also
been implicated in adaptive immunity, particularly in IS formation by cytotoxic T lymphocytes
(CTLs). NK cells have a similar mechanism of synapse formation and granule release during
target cell killing. Therefore, we hypothesise that Hh signalling plays a key role in NK cell
effector function.
This project aims to elucidate the role of Hh signalling in the development and function of NK
cells, using a novel reporter mouse line to selectively label NK cells. My work suggests that
Hh pathway components are expressed in NK cells and are upregulated upon NK cell
activation. Also, preliminary microscopy studies indicate that blocking Hh signalling
pharmacologically alters IS formation. Understanding the mechanisms by which Hh signalling
regulates NK cells may aid in developing novel cancer immunotherapies.