Influence of Age on CD4 T Memory Cells

项目总结/摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种进行性神经退行性疾病。虽然发病机制是 未解决的，神经炎症似乎发挥了贡献，甚至可能是一个致病的作用。一个最近 一项已发表的研究描述了终末分化效应T细胞在外周血中的扩增， 老年痴呆症患者，让人想起慢性感染或自身免疫性疾病的个体。 此外，AD患者脑内存在寡克隆T细胞群，包括EBV特异性T细胞 抗原基于我们目前对多种病毒抗原特异性的离体四聚体分选细胞的研究，我们 在此提出，这种抗原特异性T细胞的染色质可及性作图是一种很好的工具， 确定与非AD淀粉样蛋白阴性患者相比，他们是否具有不同的活化或分化史 个体具体来说，我们将比较EB病毒潜伏性和溶解性T细胞的染色质可及位点， 以水痘带状疱疹病毒和流感抗原作为对照。检测一种独特的染色质模式 可及性将有力地支持这些T细胞积极参与疾病过程的观点。 此外，这些位点的鉴定将使我们能够推断调控转录因子网络， 这些T细胞的分化。在第二步中，我们计划将AD患者与非AD淀粉样蛋白阳性患者进行比较， 个体以确定T细胞反应是否已经存在于疾病的早期阶段。 相反，阴性结果将强烈暗示所报告的扩张和脑浸润， 在阿尔茨海默病患者中特异性针对EBV的寡克隆T细胞群体是非特异性的。

PROJECT SUMMARY / ABSTRACT Alzheimer's disease (AD) is a progressive neurodegenerative disease. While pathogenetic mechanisms are unresolved, neuroinflammation appears to play a contributory or possibly even a causative role. A recently published study has described an expansion of terminally differentiated effector T cells in the peripheral blood of Alzheimer's patients, reminiscent of findings in individuals with chronic infection or autoimmune disease. Moreover, oligoclonal T cell population were found in the brain of AD patients, including T cells specific for EBV antigens. Based on our current studies of ex vivo tetramer-sorted cells specific for a variety of viral antigens, we propose here that chromatin accessibility mapping of such antigen-specific T cells is an excellent tool to determine whether they have a distinct activation or differentiation history compared to non-AD amyloid-negative individuals. Specifically, we will compare chromatin accessible sites in T cells specific for EBV latent and lytic antigens with varicella zoster virus and influenza antigens as controls. Detection of a unique pattern of chromatin accessibility would strongly support the notion that these T cells are actively involved in the disease process. Moreover, identification of such sites would allow us to infer transcription factor networks that regulate the differentiation of these T cells. In a second step, we plan to compare AD patients to non-AD amyloid-positive individuals to determine whether the T cell response is already present in the early stages of the disease. Conversely, a negative result would strongly imply that the reported expansion of and brain infiltration with oligoclonal T cell populations specific to EBV in Alzheimer's patients is non-specific.