The role of brain resident T cells in Alzheimer's disease

项目摘要/摘要 几十年前，在阿尔茨海默病(AD)患者的死后大脑中首次观察到T细胞，但数量很少 已知它们在疾病进展中的作用。AD的标志是特定蛋白质的寡聚，这些蛋白质可以 聚集到细胞外的斑块中，推动研究了解AD中的天然免疫细胞，因为它们 对这些斑块的反应和清除的潜力。最近的证据表明，适应性免疫细胞 在AD中发挥重要作用；AD脑内CD8 T细胞数量显著增加，而CD8 T细胞的扩张 AD患者脑脊液中记忆CD8 T细胞亚群与认知功能呈负相关。 到目前为止，小鼠的T细胞耗尽和基因敲除研究在T细胞的影响方面得出了相互矛盾的数据 在公元后。然而，长期被忽视的T细胞群体，因为他们唯一的新发现和 历史上将大脑视为免疫特权的观点是驻留在大脑中的组织驻留记忆T细胞(TRM 并处于发挥局部免疫激活的最佳位置。因为目前还没有明确的T细胞抗原 阿尔茨海默病，我们将采取一种创新的方法来模拟大脑中TRM的激活，使用一个模型 抗原。这将是第一项在阿尔茨海默病背景下检查TRM及其影响的研究 在阿尔茨海默病进展过程中以一种确定的方式激活T细胞。这项提议的目的是：1)测试 脑CD8TRM激活天然免疫细胞，包括NK细胞、小胶质细胞和巨噬细胞 阿尔茨海默病小鼠模型，II)确定脑CD8 TRM激活对阿尔茨海默病进展的影响 在小鼠中，包括认知和病理学，以及iii)确定迁移动力学、丰度和克隆 CD8TRM在小鼠和人AD脑中的表达。这些目标将通过补充经典 与OnSite持续合作研究小鼠TRM模型的免疫学技术 神经病理学家研究阿尔茨海默病和非神经受累脑组织中的T细胞 单细胞水平的组织。总的来说，这些实验将加深我们对CD8作用的理解 TRM在阿尔茨海默病中的作用，并有可能提供对其他神经疾病中T细胞功能的洞察， 揭示新的治疗靶点，并全面建立对TRM在大脑中的功能的基础了解。

PROJECT SUMMARY/ABSTRACT T cells were first observed in postmortem brains of Alzheimer’s disease (AD) patients decades ago, yet very little is known about their role in disease progression. AD is marked by oligomerization of specific proteins that can accumulate into extracellular plaques, driving research to understand innate immune cells in AD due to their potential for reacting to and clearing these plaques. More recent evidence suggests that adaptive immune cells play a significant role in AD; numbers of CD8+ T cells are significantly increased in AD brains, and expansion of a subset of memory CD8+ T cells in the cerebrospinal fluid of AD patients is negatively associated with cognition. To date, T cell depletion and knock-out studies in mice have yielded conflicting data on the influence of T cells in AD. However, a population of T cells that has long been overlooked due to their only recent discovery and the historic view of the brain as immune privilege are tissue resident memory T cells (TRM), which reside in the brain and are optimally positioned to exert local immune activation. As there is currently no defined T cell antigen in Alzheimer’s disease, we will take an innovative approach to model TRM activation in the brain using a model antigen. This will be the first study to examine TRM in context of Alzheimer’s disease and to examine the impact of T cell activation in a defined manner on AD progression. The objectives of this proposal are to i) test the ability of brain CD8+ TRM to trigger innate immune cell activation, including NK cells, microglia and macrophages, in a mouse model of AD, ii) determine the impact of brain CD8+ TRM activation on Alzheimer’s disease progression in mice, including cognition and pathology, and iii) determine the migration dynamics, abundance and clonality of CD8+ TRM in mouse and human AD brain. These goals will be attained by complementing classical immunologic techniques for studying TRM in mouse models with a continuing collaboration with onsite neuropathologists to study T cells from human postmortem tissue from AD and non-neurologically involved brain tissue at a single cell level. Collectively, these experiments will enhance our understanding of the role of CD8+ TRM in Alzheimer’s disease and has potential to provide insight into T cell functions in other neurological diseases, reveal novel therapeutic targets, and overall build a foundational understanding of TRM functions in the brain.