TRACINg: T-Cell Reactivation by Antigen Presenting Cells In the Central Nervous System

追踪：中枢神经系统中抗原呈递细胞对 T 细胞的重新激活

• 批准号: 446267576
• 负责人: Professor Dr. Ari Waisman
• 金额: --
• 依托单位: Institut für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Reinhart Koselleck Projects
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/446267576?language=en
• 关键词: TRACINg; Cell; Reactivation; Antigen; Presenting

Self-reactive T cells are central to the pathogenesis of autoimmune central nervous system (CNS) diseases, including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). To initiate an autoimmune response, antigen presenting cells (APCs) must reactive T cells within the CNS. Due to a lack of suitable tools, an unbiased analysis of the cell types that function as APCs in the CNS, and how different APCs can differentially affect T cells, has not been conducted. Addressing these questions will inform us on the underlying processes of CNS inflammation and will open new avenues for the development of targeted therapeutics for autoimmune disorders, such as MS.TRACINg will develop new, ground-breaking genetic tools to better understand the mechanism of CNS inflammation in the context of EAE and to answer the pertinent questions that current genetic models have thus far been unable to address.TRACINg is founded on two main aims: 1) to identify the specific APCs that reactivate T cells in the CNS at different stages of EAE, and 2) to trace labelled reactivated T cells after their interaction with defined APCs in the CNS to determine how APCs affect T-cell differentiation, migration and function.In Aim 1, we will use the LIPSTIC system to label, characterize and map the APCs that interact with antigen-specific T cells during reactivation in the CNS. In Aim 2, we will generate T cells that express Cre-recombinase upon antigen-specific triggering by specific APCs in the CNS. This approach will allow us to follow T cells as they migrate in and out of the CNS during neuroinflammation and to analyse the functional consequences of this interaction. These new genetic tools will not only advance neuroimmune research but will help to address the many open questions regarding the interactions between T cells and APCs in other T-cell-mediated diseases and immunological processes involving autoreactive T cells.

自身反应性T细胞是自身免疫性中枢神经系统（CNS）疾病的发病机制的核心，包括多发性硬化（MS）及其动物模型实验性自身免疫性脑脊髓炎（EAE）。为了启动自身免疫应答，抗原呈递细胞（APC）必须与CNS内的T细胞反应。由于缺乏合适的工具，尚未对CNS中充当APC的细胞类型以及不同的APC如何差异地影响T细胞进行无偏分析。解决这些问题将告知我们中枢神经系统炎症的潜在过程，并将为开发自身免疫性疾病（如MS）的靶向治疗开辟新的途径。TRACINg将开发新的，地面-打破遗传工具，以更好地了解EAE背景下CNS炎症的机制，并回答目前遗传模型迄今无法解决的相关问题。两个主要目标：1）鉴定在EAE的不同阶段在CNS中重新激活T细胞的特异性APC，和2）在标记的重新激活的T细胞与CNS中确定的APC相互作用后追踪标记的重新激活的T细胞，以确定APC如何影响T细胞分化、迁移和功能。表征和绘制在CNS中再活化期间与抗原特异性T细胞相互作用的APC。在目标2中，我们将产生在CNS中的特异性APC的抗原特异性触发后表达Cre重组酶的T细胞。这种方法将使我们能够跟踪T细胞在神经炎症期间迁移进出CNS，并分析这种相互作用的功能后果。这些新的遗传工具不仅将推进神经免疫研究，而且将有助于解决有关T细胞和APC在其他T细胞介导的疾病和涉及自身反应性T细胞的免疫过程中相互作用的许多开放性问题。