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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' 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

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-阿尔茨海默病（AD）和其他神经退行性疾病的特征是： 炎症、神经变性和CNS血管通透性增加，包括微出血 阵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一个活跃的研究领域。人们非常重视 先天免疫细胞和小胶质细胞在AD的发展中的作用。然而，适应性免疫细胞的作用， 包括CD 8 T细胞，尽管它们存在于AD患者的脑实质中，但尚未被定义。这些 最近对CD 8 T细胞库及其与疾病相关性的分析进一步强调了这一发现。 在人类AD患者中的严重性。APP/PS1小鼠显示效应子CD 8 T细胞的显著脑浸润 表型同样，我们的合作研究者，亚利桑那州马约诊所的约翰·弗莱尔博士，也观察到了显著的 在他的新型rAAV引发的tau蛋白病小鼠模型中的CD 8 T细胞脑浸润。使用我们的新型MHC I类 条件性基因敲除小鼠，我们已经确定巨噬细胞和树突状细胞引发非等效 CD 8 T细胞对PbA感染的应答当两种抗原呈递细胞都引发CD 8 T细胞时， 当CD 8 T细胞浸润脑组织时，只有树突状细胞引起的CD 8 T细胞才能诱导致命的血脑屏障 破坏我们的中心假设是克隆扩增的CD 8 T细胞参与脑血管系统， 在浸润过程中迁移的抗原呈递细胞，其有助于神经病理学， AD和Tau病的认知缺陷。我们计划通过执行 具体目标如下： 具体目标1 -定义APP/PS1中产生的CD 8 T细胞库和表型， Tau病小鼠通过转录谱。 具体目标2 -确定驻留和迁移APC在启动和启用CNS中的关键作用 APP/PS1和Tau病小鼠模型中CD 8 T细胞应答的浸润 具体目标3 -剖析CD 8 T细胞所需的关键的表达MHC I类的CNS细胞类型 诱发的神经病理学和认知缺陷 这项工作是创新的，因为它利用了我们独特的转基因小鼠模型， 方法学，以及马约诊所研究项目的新核心设施。我们的目标是定义 从机械上讲，CD 8 T细胞在人类痴呆症中的作用是通过使用领先的 实验模型除了采用的创新方法之外，抗原提呈的概念 细胞引起差异性CD 8 T细胞应答是非常新颖的，需要进一步研究其机制 这是治疗靶向的。如果CD 8 T细胞引发和参与免疫应答， 由特定细胞类型呈递的抗原促进神经病理学和行为缺陷。