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

获得资助的项目摘要 阿尔茨海默病(AD)和其他神经退行性疾病的特点是 炎症、神经变性和中枢神经系统血管通透性，包括微出血形成。这个 特定免疫细胞类型在阿尔茨海默病和其他神经病相关基础神经病理中的作用 疾病仍然是一个活跃的研究领域。先天免疫的作用受到了极大的关注。 细胞和小胶质细胞在AD发病中的作用。然而，包括CD8 T在内的获得性免疫细胞的作用 细胞，尽管它们存在于AD患者的脑实质中，但尚未被定义。这些发现是 最近对CD8 T细胞谱系的分析及其与疾病严重程度的相关性进一步突显了这一点 人类AD患者。APP/PS1小鼠脑组织中有大量CD8T细胞的效应表型。 同样，我们的合作研究员，亚利桑那州梅奥诊所的约翰·弗莱尔博士也观察到了显著的CD8 T细胞 他在新奇的rAAV中启动了脑部浸润的多动症小鼠模型。使用我们的新MHC I类有条件 在基因敲除的小鼠中，我们已经确定巨噬细胞和树突状细胞激活了不等同的CD8T细胞 回应。虽然这两种抗原提呈细胞都能刺激CD8T细胞的反应，但只有CD8T 树突状细胞产生的细胞会导致致命的血脑屏障破坏。我们的核心假设是 克隆性扩增的CD8T细胞与脑血管和迁移性抗原提呈细胞结合 导致阿尔茨海默病和肌萎缩侧索硬化症的神经病理和认知缺陷的渗透。我们计划 通过执行以下具体目标来检验这一中心假设： 特定目标1-确定APP/PS1和APP/PS1产生的CD8T细胞谱系和表型(S) 通过转录图谱研究小鼠的自闭症。 具体目标2--确定居留和迁徙的APC在启动和启动中枢神经系统中的关键作用 APP/PS1和tau病小鼠模型中CD8 T细胞反应的浸润 特定目标3-剖析CD8T细胞所需的关键MHC-I类表达CNS细胞类型 诱发性神经病理与认知功能障碍 这项拟议的工作具有创新性，因为它利用了我们独特的转基因小鼠模型，即新颖的成像 方法，以及我们在梅奥诊所的研究计划可用的新核心设施。我们的目标是定义 CD8 T细胞在人类痴呆中的作用机制研究 实验模型。除了采用的创新方法外，抗原呈递的概念 细胞提高CD8T细胞的差异性反应是非常新颖的，值得进一步研究其机制 这在治疗上是有针对性的。这一点尤其重要，如果CD8 T细胞启动和参与 由特定细胞类型呈递的抗原促进了神经病理和行为缺陷。

SUMMARY OF THE FUNDED PROJECT 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. 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.