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

点击翻译按钮获取中文摘要

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 effectorcells peripherally. Specific NK cell killing is achieved through expression of a number ofgermline-encoded receptors. Following receptor ligation, NK cells form an immunologicalsynapse (IS) with target cells to allow polarised secretion of cytotoxic granules whilstminimising bystander killing. Recently, NK cells became attractive as cancer immunotherapytargets due to their capacity to lyse cancer cells without prior sensitisation.Despite thorough characterisation of NK cell receptor signalling pathways, intracellularpathways are less well understood. The hedgehog (Hh) signalling pathway is known to havean important role during embryogenesis and adult tissue maintenance. Hh signalling has alsobeen 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 duringtarget cell killing. Therefore, we hypothesise that Hh signalling plays a key role in NK celleffector function.This project aims to elucidate the role of Hh signalling in the development and function of NKcells, using a novel reporter mouse line to selectively label NK cells. My work suggests thatHh pathway components are expressed in NK cells and are upregulated upon NK cellactivation. Also, preliminary microscopy studies indicate that blocking Hh signallingpharmacologically alters IS formation. Understanding the mechanisms by which Hh signallingregulates NK cells may aid in developing novel cancer immunotherapies.