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Role of cell cannibalism and non-canonical autophagy in antigen presentation: implications in T-cell selection and immune homeostasis

细胞同类相食和非典型自噬在抗原呈递中的作用：对 T 细胞选择和免疫稳态的影响

基本信息

批准号：
1804833
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：
2016
资助国家：
英国
起止时间：
2016 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=studentship-1804833
关键词：
Role cell cannibalism non canonical

项目摘要

Theme: Bioscience for HealthAntigen acquisition and presentation is a vital part of the immune system which allows cells to distinguish self from non-self and mount a protective T-cell response against invading pathogens. Cells use a variety of mechanisms of acquiring antigens, involving the uptake of intracellular and extracellular material. This project will study the role of cell cannibalism in the acquisition and presentation of antigen in the context of T-cell selection. Cell cannibalism is a mechanism in which entire live cells are engulfed by other cells, resulting in the formation of cell-in-cell structures (1), and is a core interest of the Florey lab at the Babraham Institute (http://www.babraham.ac.uk/our-research/signalling/oliver-florey) . Examples of cell-in-cell structures are found in a variety of diseases (2, 3), but importantly also occur in physiological settings between thymocytes and epithelial nurse cells during T cell development in the thymus (4) and even between the embryo and uterus during implantation (5). In these examples, internalized cells can escape their engulfment, but more commonly their fate is death which involves the activation of a non-canonical autophagy pathway that promotes the lipidation of the protein LC3 to the vacuole housing the internalized cell (6-8).This project will test the hypothesis that cell cannibalism can act as a route of antigen presentation and can be regulated by a non-canonical autophagy pathway. This would potentially have major implications in shaping the immune repertoire by controlling T cell selection and therefore participate in generating an immune system capable of responding to infection while maintaining immune tolerance.The main aims will include the development and characterization of cell-cell interactions in model systems of cell cannibalism using microscopy based techniques. This will utilize existing cell cannibalism models of cultured human epithelial cells and the establishment of new models of primary mouse thymocytes interacting with a thymic nurse cell line. These systems will then be manipulated where by internalized cells are loaded with ovalbumin antigen, and subsequent presentation of antigen by hosts cells monitored using ovalbumin-specific T cells. Different aspects of cell-in-cell formation and fate will be manipulated to test for an effect on antigen presentation. The role of autophagy in cell-in-cell mediated antigen presentation will be tested using gene editing reagents developed by the lab that specifically inhibit non-canonical autophagy.This project will combine immunology and cell biology expertise and provide a strong training in cell biology techniques, with an emphasis on microscopy, and molecular biology, including CRISPR/Cas9 gene editing. Expected results will have impacts on our understanding of how T cells are selected and the molecular pathways underlying this important homeostatic event.

布景主题：抗原的获取和呈递是免疫系统的重要组成部分，它允许细胞区分自我和非自我，并对入侵的病原体产生保护性T细胞反应。细胞利用多种机制获得抗原，包括细胞内和细胞外物质的摄取。本计画将研究在T细胞选择的背景下，细胞自食在抗原的获得和呈递中所扮演的角色。细胞自相残杀是一种机制，其中整个活细胞被其他细胞吞噬，导致细胞中细胞结构的形成（1），并且是Babraham研究所Florey实验室的核心兴趣（http：//www.babraham.ac.uk/our-research/signalling/oliver-florey）。细胞中细胞结构的例子存在于多种疾病中（2，3），但重要的是，也发生在胸腺中T细胞发育期间胸腺细胞和上皮营养细胞之间的生理环境中（4），甚至胚胎和子宫之间植入期间（5）。在这些例子中，内化的细胞可以逃脱它们的吞噬，但更常见的是它们的命运是死亡，这涉及非经典自噬途径的激活，该途径促进蛋白LC 3脂化到容纳内化细胞的液泡（6-8）。这将有可能通过控制T细胞的选择，从而参与产生一个免疫系统，能够响应感染，同时保持免疫tolerance.The主要目标将包括使用显微镜为基础的技术在细胞自食模型系统中的细胞-细胞相互作用的发展和表征的免疫系统塑造免疫库的重大影响。这将利用现有的细胞自食模型培养的人上皮细胞和建立新的模型的原代小鼠胸腺细胞与胸腺护士细胞系相互作用。然后操作这些系统，其中内化的细胞负载有卵清蛋白抗原，随后使用卵清蛋白特异性T细胞监测宿主细胞对抗原的呈递。将操作细胞中细胞形成和命运的不同方面，以测试对抗原呈递的影响。自噬在细胞中细胞介导的抗原呈递中的作用将使用实验室开发的基因编辑试剂进行测试，该试剂可以特异性抑制非经典自噬。该项目将联合收割机结合免疫学和细胞生物学专业知识，并提供细胞生物学技术的强大培训，重点是显微镜和分子生物学，包括CRISPR/Cas9基因编辑。预期的结果将对我们理解T细胞是如何被选择的以及这一重要的稳态事件背后的分子途径产生影响。