Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease
Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer's disease
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DOI：
10.1038/s41586-019-1895-7
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发表时间：
2020-01-08
期刊：
影响因子：
64.8
通讯作者：
Wyss-Coray, Tony
中科院分区：
文献类型：
--
作者：
Gate, David;Saligrama, Naresha;Wyss-Coray, Tony
对几个队列的综合分析显示，在阿尔茨海默病患者的脑脊液中发现了克隆的抗原经历T细胞，这表明适应性免疫系统在年龄相关的神经退行性疾病中发挥作用。阿尔茨海默病是一种无法治愈的神经退行性疾病，其中神经炎症具有关键作用（1）。然而，人们对阿尔茨海默病中适应性免疫反应的贡献知之甚少（2）。在这里，使用多个队列的综合分析，我们确定阿尔茨海默病的外周和中枢适应性免疫变化。首先，我们对外周血单核细胞进行了大量细胞计数，发现了阿尔茨海默病的免疫特征，包括CD 8（+）T效应记忆CD 45 RA（+）（T-EMRA）细胞数量的增加。在第二个队列中，我们发现CD 8（+）T-EMRA细胞与认知呈负相关。此外，单细胞RNA测序显示，T细胞受体（TCR）信号在这些细胞中增强。值得注意的是，通过在第三个队列中使用几种单细胞TCR测序策略，我们在阿尔茨海默病患者的脑脊液中发现了克隆扩增的CD 8（+）T-EMRA细胞。最后，我们使用机器学习、克隆和肽筛选来证明阿尔茨海默病患者脑脊液中克隆扩增的TCR对两种不同的EB病毒抗原的特异性。这些结果揭示了阿尔茨海默病血液和脑脊液中的适应性免疫反应，并提供了克隆的抗原经历的T细胞巡逻受年龄相关神经变性影响的大脑鞘内空间的证据。
An integrated analysis of several cohorts shows that clonal, antigen-experienced T cells are found in the cerebrospinal fluid of patients with Alzheimer's disease, suggesting that the adaptive immune system has a role in age-related neurodegeneration.Alzheimer's disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function(1). However, little is known about the contribution of the adaptive immune response in Alzheimer's disease(2). Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer's disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer's disease that consists of increased numbers of CD8(+) T effector memory CD45RA(+) (T-EMRA) cells. In a second cohort, we found that CD8(+) T-EMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8(+) T-EMRA cells in the cerebrospinal fluid of patients with Alzheimer's disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer's disease to two separate Epstein-Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer's disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.