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

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 - 补充

• 批准号: 10836880
• 负责人: Aaron J Johnson
• 金额: $ 6.13万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-07 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10836880
• 关键词: APP-PS1; Alzheimer' s Disease; Alzheimer' s disease patient; Antigen Presentation; Antigen-Presenting Cells; Antigens; Area; Arizona; Attention; Behavioral; Brain; CD8-Positive T-Lymphocytes; Cells; Cerebrovascular system; Clinic; Clonal Expansion; Cognitive deficits; Core Facility; Dementia; Dendritic Cells; Development; Dissection; Experimental Models; Funding; Gene Expression Profiling; Goals; Hemorrhage; Human; Image; Immune; Infiltration; Inflammation; Investigation; Knockout Mice; Knowledge; MHC Class I Genes; Macrophage; Methodology; Microglia; Mus; Nerve Degeneration; Phenotype; Recombinant adeno-associated virus (rAAV); Research; Research Personnel; Role; Severity of illness; T cell response; Tauopathies; Testing; Therapeutically Targetable; Transgenic Mice; Vascular Permeabilities; Work; blood-brain barrier disruption; brain cell; brain parenchyma; cell type; conditional knockout; effector T cell; innovation; mouse model; nervous system disorder; neuropathology; novel; programs

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.

资助项目概要 阿尔茨海默氏病（AD）和其他神经退行性病症的特征在于， 炎症、神经变性和CNS血管通透性，包括微出血形成。的 特定免疫细胞类型在与AD和其他神经系统疾病相关的潜在神经病理学中的作用 疾病仍然是一个活跃的研究领域。先天性免疫在免疫系统中的作用受到了极大的关注。 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，包括CD 8 T细胞， 细胞，还没有被定义，尽管它们存在于AD患者的脑实质中。这些发现 最近对CD 8 T细胞库的分析以及与疾病严重程度的相关性进一步强调了这一点， 人类AD患者。APP/PS1小鼠显示效应表型的CD 8 T细胞的显著脑浸润。 同样，我们的合作研究者，亚利桑那州马约诊所的John Fryer博士，也观察到显著的CD 8 T细胞 在他的新型rAAV引发的tau蛋白病小鼠模型中的脑浸润。使用我们的新型MHC I类条件 在敲除小鼠中，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， 应答虽然这两种抗原呈递细胞都引发了浸润大脑的CD 8 T细胞应答，但只有CD 8 T细胞应答， 由树突状细胞产生的细胞诱导致命的血脑屏障破坏。我们的核心假设是 克隆扩增的CD 8 T细胞参与脑血管系统和迁移性抗原呈递细胞， 在AD和Tau病中，其导致神经病理学和认知缺陷。我们计划 通过执行以下具体目标来检验这一中心假设： 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 实验模型除了所采用的创新方法，抗原呈递的概念 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 这是治疗上可针对的。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。

项目成果

TREM2 mediates MHCII-associated CD4+ T cell response against gliomas.

TREM2 介导 MHCII 相关 CD4 T 细胞针对神经胶质瘤的反应。

• DOI: 10.1093/neuonc/noad214
• 发表时间: 2023
• 期刊: Neuro-oncology
• 影响因子: 15.9
• 作者: Zheng,Jiaying;Wang,Lingxiao;Zhao,Shunyi;Zhang,Wenjing;Chang,Yuzhou;Bosco,DaleB;Huang,Tao;Dheer,Aastha;Gao,Shan;Xu,Shengze;Ayasoufi,Katayoun;Al-Kharboosh,Rawan;Qi,Fangfang;Xie,Manling;Johnson,AaronJ;Dong,Haidong;Quiñones-H
• 通讯作者: Quiñones-H