Hedgehog signalling in CD8 Tcell memory differentiation

Hedgehog （Hh）信号在胚胎发育和成体组织维持过程中起着重要作用。在免疫系统中Hh通路参与胸腺T细胞的发育。直到最近，人们还不清楚Hh通路在成熟T细胞中是活跃的还是必需的。成熟的naïve外周CD8T细胞没有终末分化。在病原体或肿瘤攻击naïve时，T细胞可以发育成高效的杀伤细胞（细胞毒性T淋巴细胞，CTL）和几个长寿命记忆亚群，这些亚群可以自我更新并在再次攻击时持续保护宿主。有趣的是，de la Roche博士的工作表明，由T细胞受体启动的Hh信号传导对CTL杀伤至关重要（de la Roche等人，Science 2013）。Hh信号是否也调节CD8记忆细胞的形成、维持和功能能力尚不清楚。该项目的目的是通过体内报告和条件敲除小鼠模型来确定CD8记忆细胞中Hh信号传导的功能相关性。我们的目标是利用组织培养和原代淋巴细胞的遗传操作结合流式细胞术、基本细胞生物学和生物化学技术来补充体内系统。在阐明引导记忆形成和功能的信号通路方面的进展将指导感染、癌症免疫治疗和疫苗开发的治疗方法。

Hedgehog (Hh) signalling plays an important role during embryonic development and adult tissue maintenance. In the immune system the Hh pathwayis involved in thymic T cell development. Until recently it was unclear whether the Hh pathway is active or required in mature T cells. Mature naïve CD8T cells in the periphery are not terminally differentiated. Upon pathogen or tumour challenge naïve T cells can develop into highly effective killer cells(Cytotoxic T Lymphocytes, CTL) and several long-lived memory subsets that self-renew and persist to protect the host upon re-challenge. Interestingly,the work of Dr. de la Roche showed that Hh signalling, initiated by the T cell receptor, is crucial for CTL killing (de la Roche et al, Science 2013).Whether Hh signalling also regulates CD8 memory cell formation, maintenance and functional capacity is unknown. The aim of this project is todetermine the functional relevance of Hh signalling in CD8 memory cells using in vivo reporter and conditional knockout mouse models. We aim tocomplement the in vivo systems with the use of tissue culture and genetic manipulation of primary lymphocytes combined with flow cytometry, basiccell biology and biochemistry techniques. Advances in elucidating the signalling pathways that guide memory formation and function will guidetherapeutic approaches to infection, cancer immunotherapy, and vaccine development.