Clonally expanded CD8 T cells patrol Alzheimer's cerebrospinal fluid [CSF]

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder in which neuroinflammation plays a critical function. Recurring viral infections and loss of immune competence increase risk for developing AD, yet the cellular and molecular mechanisms driving these immune changes are unknown. Here we performed mass cytometry of peripheral blood mononuclear cells and detected an immunologic signature of AD characterized by increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. CD8+ TEMRA cells were negatively associated with cognition and single cell RNA sequencing revealed their cytotoxic effector function. Strikingly, we discovered identical, shared T cell receptors (TCRs) of clonally expanded CD8+ TEMRA cells in cerebrospinal fluid (CSF) of three AD patients. Deep TCR sequencing, machine learning, and peptide screens identified the HLA-B*08:01-restricted Epstein-Barr virus trans-activator protein BZLF1 as the cognate antigen of a novel AD CSF TCR . These results provide the first evidence of clonal, antigen-specific T  cells patrolling the intrathecal space of brains affected by age-related neurodegeneration Examination of transcriptional profile of cells from the cerbrospinal fluid of healthy and diseased patients. AD = Alzheimer's disease MCI = mild cognitive impairment HC = healthy control

阿尔茨海默病（Alzheimer’s disease, AD）是一种与年龄相关的神经退行性疾病，神经炎症在其中发挥关键调控作用。复发性病毒感染与免疫功能衰退会增加AD的发病风险，但驱动这些免疫改变的细胞及分子机制尚未明确。本研究对外周血单个核细胞（peripheral blood mononuclear cells）开展质谱流式细胞术（mass cytometry）分析，检测到AD具有以CD8+ T效应记忆CD45RA+（TEMRA）细胞数量增多为特征的免疫学特征。CD8+ TEMRA细胞数量与认知功能呈负相关，单细胞RNA测序（single cell RNA sequencing）揭示了其细胞毒性效应功能。值得注意的是，本研究在3名AD患者的脑脊液（cerebrospinal fluid, CSF）中发现了克隆扩增的CD8+ TEMRA细胞所共有的相同T细胞受体（T cell receptors, TCRs）。通过深度TCR测序、机器学习与肽段筛选，本研究确定了HLA-B*08:01限制性EB病毒（Epstein-Barr virus）反式激活蛋白BZLF1为一种新型AD脑脊液TCR的同源抗原。本研究结果首次提供证据表明，克隆性、抗原特异性T细胞会在受年龄相关神经退行性病变累及的大脑鞘内区域进行巡逻。此外，本研究还对健康受试者与疾病患者脑脊液中的细胞转录组特征进行了分析。缩写说明：AD=阿尔茨海默病（Alzheimer's disease），MCI=轻度认知障碍（mild cognitive impairment），HC=健康对照（healthy control）