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Hedgehog signalling in CD8 Tcell memory differentiation

CD8 T 细胞记忆分化中的 Hedgehog 信号传导

基本信息

批准号：
1954837
负责人：
金额：
--
依托单位：
University of Cambridge
依托单位国家：
英国
项目类别：
Studentship
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1954837
关键词：
Hedgehog signalling CD8 Tcell memory

项目摘要

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.

Hedgehog (Hh) 信号在胚胎发育和成体组织维持过程中发挥着重要作用。在免疫系统中，Hh 通路参与胸腺 T 细胞的发育。直到最近，尚不清楚 Hh 通路在成熟 T 细胞中是否活跃或是否必需。外周成熟的幼稚 CD8T 细胞未终末分化。在病原体或肿瘤的攻击下，幼稚 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）和一些长寿命的记忆子集，这些子集可以自我更新，并在再次受到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 信号传导对于 CTL 杀伤至关重要（de la Roche 等人，Science 2013）。Hh 信号传导是否也调节 CD8 记忆细胞的形成、维持和功能能力尚不清楚。该项目的目的是使用体内报告基因和条件敲除小鼠模型确定 CD8 记忆细胞中 Hh 信号传导的功能相关性。我们的目标是通过使用组织培养和原代淋巴细胞的遗传操作并结合流式细胞术、基础细胞生物学和生物化学技术来补充体内系统。阐明指导记忆形成和功能的信号通路的进展将指导感染、癌症免疫治疗和疫苗开发的治疗方法。