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

自然杀伤细胞（NK）是先天免疫细胞，在抗病毒和抗肿瘤免疫中起着至关重要的作用。NK细胞在外周血成熟为细胞毒性效应细胞之前在骨髓中发育。特异性NK细胞杀伤是通过表达一些种系编码受体实现的。受体结扎后，NK细胞与靶细胞形成免疫突触（IS），允许细胞毒性颗粒的极化分泌，同时最大限度地减少旁观者的杀伤。最近，NK细胞成为有吸引力的癌症免疫治疗靶点，因为它们能够在没有事先致敏的情况下溶解癌细胞。尽管彻底表征NK细胞受体信号通路，细胞内通路尚不清楚。众所周知，hedgehog （Hh）信号通路在胚胎发生和成体组织维持过程中起着重要作用。Hh信号也与适应性免疫有关，特别是在细胞毒性T淋巴细胞（ctl）形成IS时。NK细胞在杀伤靶细胞过程中具有类似的突触形成和颗粒释放机制。因此，我们假设Hh信号在NK细胞效应物功能中起关键作用。本项目旨在阐明Hh信号在NK细胞发育和功能中的作用，使用一种新的报告小鼠系选择性地标记NK细胞。我的工作表明，athh通路成分在NK细胞中表达，并在NK细胞活化时上调。此外，初步的显微镜研究表明，阻断Hh信号从药理学上改变IS的形成。了解Hh信号调节NK细胞的机制可能有助于开发新的癌症免疫疗法。

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.