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

项目总结/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，但很少 已知它们在疾病进展中的作用。AD的特征是特异性蛋白质的寡聚化， 积累成细胞外斑块，推动研究了解AD中的先天免疫细胞， 可能对这些斑块产生反应并清除这些斑块。最近的证据表明，适应性免疫细胞 在AD中发挥重要作用; AD脑中CD 8 + T细胞的数量显著增加， AD患者脑脊液中的记忆性CD 8 + T细胞亚群与认知呈负相关。 迄今为止，小鼠T细胞耗竭和敲除研究在T细胞的影响方面产生了相互矛盾的数据。 在AD中。然而，长期以来一直被忽视的T细胞群体，由于它们最近才被发现， 将大脑视为免疫豁免的历史观点是组织驻留记忆T细胞（TRM），其驻留在大脑中 并且被最佳地定位以发挥局部免疫激活。由于目前没有确定的T细胞抗原， 阿尔茨海默病，我们将采取创新的方法，使用模型模拟大脑中的TRM激活 抗原的这将是第一个研究TRM在阿尔茨海默病的背景下，并检查其影响， T细胞活化在AD进展中的作用。本提案的目标是：i）测试 脑CD 8 + TRM触发先天性免疫细胞激活，包括NK细胞，小胶质细胞和巨噬细胞，在一个 AD的小鼠模型，ii）确定脑CD 8 + TRM活化对阿尔茨海默病进展的影响 包括认知和病理学，和iii）确定迁移动力学、丰度和克隆性 CD 8 + TRM在小鼠和人类AD脑中的表达。这些目标将通过补充经典 免疫学技术研究TRM在小鼠模型中的持续合作， 神经病理学家研究来自AD和非神经系统受累大脑的人类死后组织的T细胞 在单细胞水平上。总的来说，这些实验将增强我们对CD 8+的作用的理解。 TRM在阿尔茨海默病中的应用，并有可能为其他神经系统疾病中的T细胞功能提供见解， 揭示新的治疗靶点，并全面了解TRM在大脑中的功能。

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.