Kinetics and Mechanisms of Steady-State Dendritic Cell Migration

稳态树突状细胞迁移的动力学和机制

基本信息

  • 批准号:
    413562856
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    德国
  • 项目类别:
    Research Grants
  • 财政年份:
    2018
  • 资助国家:
    德国
  • 起止时间:
    2017-12-31 至 2021-12-31
  • 项目状态:
    已结题

项目摘要

Dendritic cells (DCs) are professional antigen presenting cells primarily responsible for the initiation of new immune or tolerogenic responses. They act as a crucial link between the innate and adaptive immune systems. DC migration from peripheral tissues into lymph nodes can be induced by inflammatory stimuli and this process is crucial for the induction of immune responses. However, in steady-state, DC migration occurs constitutively and has an important role in the initiation of peripheral immunological tolerance - a process crucial for the prevention of deleterious inflammation. This is most notable in the intestine, where a failure of peripheral tolerance can lead to the development of inflammatory bowel diseases (IBD) or food allergy. Surprisingly, the mechanisms controlling DC migration in steady state and thereby tolerogenic immune responses are largely unknown.To mechanistically dissect the process of steady state DC migration, we developed a range of novel, dedicated tools. Cannulation of the pseudo-afferent lymph will allow us to isolate DCs in the process of migration, while a novel transgenic mouse model, the CCR7-GFP reporter, enables the identification of DCs which are about to exit peripheral tissues. In addition, using in vivo photoconversion, we will be able to track and quantify DC migration. Our initial results show that steady-state intestinal DC migration is a highly dynamic process which leads to the almost complete turnover of the migratory DC compartment in intestine-draining lymph nodes every 24h. This remarkable investment of resources further underlines the importance of steady-state DC migration. Furthermore, we found that intestinal DCs, in the stages immediately preceding egress from tissue, already adopt a distinct phenotype. Characterising these initial changes will enable us to dissect the molecular mechanisms controlling the process of DC migration. In this proposal we aim to: 1) Determine the kinetics of steady-state DC life cycle 2) Characterise the molecular mechanisms controlling steady-state DC migration. 3) Determine the fate, location and function of steady-state migrating DCs in the LN. This project will generate a comprehensive model of steady state DC migration and its regulation. We expect that such understanding, in addition to characterizing a major biological process, may provide information that will affect the future development and design of treatments for inflammatory diseases, particularly in the context of the intestinal tract.
树突状细胞(Dendritic cells,DC)是专职抗原呈递细胞,主要负责启动新的免疫或耐受性应答。它们是先天免疫系统和适应性免疫系统之间的重要联系。DC从外周组织迁移到淋巴结中可以由炎症刺激诱导,并且该过程对于诱导免疫应答至关重要。然而,在稳态下,DC迁移组成性地发生,并且在外周免疫耐受的起始中具有重要作用-这是预防有害炎症的关键过程。这在肠道中最明显,其中外周耐受性的失败可导致炎症性肠病(IBD)或食物过敏的发展。令人惊讶的是,在稳态下控制DC迁移的机制,从而致耐受性免疫应答在很大程度上是unknowed.To机械解剖的过程中的稳态DC迁移,我们开发了一系列新的,专用的工具。插管的假传入淋巴将使我们能够分离的DC在迁移的过程中,而一种新的转基因小鼠模型,CCR 7-GFP报告,使DC的鉴定即将退出外周组织。此外,使用体内光转换,我们将能够跟踪和量化DC迁移。我们的初步研究结果表明,稳态肠道DC迁移是一个高度动态的过程,导致几乎完全营业额的迁移DC隔室在结肠引流淋巴结每24小时。这一显著的资源投资进一步强调了稳定状态的DC迁移的重要性。此外,我们发现,肠树突状细胞,在即将从组织出口之前的阶段,已经采取了独特的表型。表征这些初始变化将使我们能够剖析控制DC迁移过程的分子机制。在这个提议中,我们的目标是:1)确定稳态DC生命周期的动力学2)表征控制稳态DC迁移的分子机制。3)确定LN中稳态迁移DC的命运、位置和功能。该项目将生成稳态DC迁移及其调节的综合模型。我们期望,这种理解,除了表征一个主要的生物过程,可能会提供信息,将影响未来的发展和设计的治疗炎症性疾病,特别是在肠道的背景下。

项目成果

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Dr. Vuk Cerovic, Ph.D.其他文献

Dr. Vuk Cerovic, Ph.D.的其他文献

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