Defining MHC class I restricted antigen presentation to CD8 T cells in experimental AD and Tauopathy

定义实验性 AD 和 Tau 病中 MHC I 类限制性抗原呈递至 CD8 T 细胞

基本信息

批准号：
10229223
负责人：
Aaron J Johnson
金额：
$ 193.37万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229223
关键词：
APP-PS1 Ablation Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease patient Antigen Presentation Antigen-Presenting Cells Antigens Area Arizona Attention Authorship Behavioral Biological Models Blood - brain barrier anatomy Brain CD4 Positive T Lymphocytes CD69 antigen CD8-Positive T-Lymphocytes CD8B1 gene Cells Cellular biology Cerebrovascular system Clinic Cognitive deficits Collaborations Core Facility Dementia Dendritic Cells Development Disease Dissection Documentation Environment Experimental Models Funding Gene Expression Gene Expression Profiling Goals Grant Granzyme Histocompatibility Antigens Class I Human Image Immune Infection Infiltration Inflammation Investigation Joints Knockout Mice Knowledge MHC Class I Genes Magnetic Resonance Imaging Manuscripts Mechanics Methodology Microglia Modeling Monitor Mus NIH Program Announcements Nerve Degeneration Neurologic Neurons Parents Patients Phenotype Proteins Recombinant adeno-associated virus (rAAV)Research Research Personnel Role Seminal Severity of illness System T cell response T-Lymphocyte Subsets Tauopathies Technology Testing Transgenic Mice Vascular Permeabilities Well in self Work blood-brain barrier disruption brain cell brain parenchyma cell type cerebral atrophy conditional knockout design effector T cell innovation macrophage mouse model nervous system disorder neuroinflammation neuropathology novel perforin programs response role model therapeutic target

项目摘要

ABSTRACT - Alzheimer’s disease (AD) and other neurodegenerative conditions are characterized by heightened inflammation, neurodegeneration, and CNS vascular permeability, including microhemorrhage formation. The role of specific immune cell types in the underlying neuropathology associated with AD and other neurologic diseases remains an active area of research. Significant attention has been given to the role of innate immune cells and microglia in the development of AD. However, the role of adaptive immune cells, including CD8 T cells, has not been defined despite their presence in brain parenchyma of AD patients. These findings were further accentuated by the recent analysis of CD8 T cell repertoire and correlation with disease severity in human AD patients. APP/PS1 mice revealed significant brain infiltration of CD8 T cells of effector phenotype. Similarly, our Co-investigator, Dr. John Fryer of Mayo Clinic Arizona, has also observed significant CD8 T cell brain infiltration in his novel rAAV initiated tauopathy mouse model. Using our novel MHC class I conditional knockout mice, we have determined that macrophages and dendritic cells prime non-equivalent CD8 T cell responses in response to PbA infection. While both antigen presenting cells prime CD8 T cell response that infiltrate the brain, only CD8 T cells raised by dendritic cells induce lethal blood-brain barrier disruption. Our central hypothesis that clonally expanded CD8 T cells engage brain vasculature and migratory antigen presenting cells during infiltration which contributes to neuropathology and cognitive deficits in AD and Tauopathies. We plan to test this central hypothesis through execution of the following specific aims: Specific Aim 1 – Define the CD8 T cell repertoire and phenotype(s) generated in APP/PS1 and Tauopathy mice through transcriptional profiling. Specific Aim 2 – Determine critical role of residential and migratory APCs in priming and enabling CNS infiltration of CD8 T cell responses in APP/PS1 and Tauopathy mouse models Specific Aim 3 – Dissect the critical MHC class I expressing CNS cell type required for CD8 T cell induced neuropathology and cognitive deficits The proposed work is innovative because it capitalizes on our unique transgenic mouse models, novel imaging methodology, and new core facilities available to our research program at Mayo Clinic. Our goal is to define mechanistically the contribution of CD8 T cells in human dementia through knowledge gained using leading experimental models. Beyond the innovative methodology employed, the concept that antigen presenting cells raise differential CD8 T cell responses is highly novel and warrants further investigation to a mechanism which is therapeutically targetable. This is especially important if CD8 T cell priming and engagement of antigen presented by specific cell types is promoting neuropathology and behavioral deficits.

摘要 - 阿尔茨海默氏病（AD）和其他神经退行性疾病的特征是增强的注射，神经退行性和中枢神经系统血管渗透性，包括微射击形成。特定免疫细胞类型在与AD相关的潜在神经病理学中的作用其他神经系统疾病仍然是研究的活跃领域。对角色的重大关注 AD开发中的先天免疫细胞和小胶质细胞。但是，适应性免疫细胞的作用，包括CD8 T细胞在内，尚未定义它们在AD患者脑实质中的存在。这些 CD8 T细胞库的最新分析和与疾病的相关性进一步加剧了发现人类广告患者的严重程度。 APP/PS1小鼠揭示了效应子CD8 T细胞的明显脑浸润表型。同样，我们的共同投资者亚利桑那州梅奥诊所的约翰·弗莱尔（John Fryer）博士也观察到了重要的 CD8 T细胞脑浸润在他的新型RAAV中启动了Tauopathy小鼠模型。使用我们的小说MHC I类有条件的敲除小鼠，我们已经确定巨噬细胞和树突状细胞主要非等量响应PBA感染的CD8 T细胞反应。而两个抗原呈现细胞的主要CD8 T细胞浸润大脑的反应，只有树突状细胞饲养的CD8 T细胞诱导致命的血脑屏障破坏。我们的中心假设是克隆扩展的CD8 T细胞参与脑脉管系统和浸润过程中迁移抗原的细胞有助于神经病理学和认知在AD和Tauopath中定义。我们计划通过执行该假设来检验这一中心假设遵循特定目的：特定目标1 - 定义在App/PS1和通过转录分析的陶氏病小鼠。具体目标2 - 确定居民和迁徙APC在启动和启用中枢神经系统中的关键作用 APP/PS1和Tauopathy小鼠模型中CD8 T细胞响应的浸润特定目标3 - 剖析CD8 T细胞所需的CNS细胞类型的关键MHC I类诱发神经病理学和认知缺陷拟议的工作具有创新性，因为它利用了我们独特的转基因鼠标模型，新颖的成像我们在Mayo Clinic的研究计划可用的方法和新的核心设施。我们的目标是定义从机械上讲，人类痴呆中CD8 T细胞在人类痴呆症中的贡献，通过使用领先的知识获得实验模型。除了进行创新的方法论，抗原提出的概念细胞提出差异CD8 T细胞反应是高度新颖的，并需要进一步研究机制如果CD8 T细胞启动和参与特定细胞类型提出的抗原正在促进神经病理学和行为缺陷。