B cells promote Alzheimers disease via cytolytic CD8+ T cells

B 细胞通过溶细胞 CD8 T 细胞促进阿尔茨海默病

• 批准号: 10913115
• 负责人: Arya Biragyn
• 金额: $ 44.7万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10913115
• 关键词: APP-PS1; Adenosine; Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Amyloid; Antigens; B-Lymphocytes; Brain; CD8-Positive T-Lymphocytes; Complex; Dementia; Deposition; Development; Disease; Disease associated microglia; Early Onset Alzheimer Disease; Event; Generations; Human; Mediating; Memory; Microglia; Mus; Nature; Neuronal Dysfunction; Pathogenicity; Pathologic; Peptides; Peripheral; Play; Publications; Reporting; Role; Synapses; T cell infiltration; Tauopathies; Tissues; Vaccines; Work; adaptive immunity; astrogliosis; brain parenchyma; combat; ecto-nucleotidase; exhaust; neurotoxic; therapeutically effective

According to the prevailing Amyloid cascade hypothesis, Alzheimers disease (AD) is caused by decades-long deposition of neurotoxic amyloid Ab-peptide aggregates (Ab plaques) in the brain. It leads to a chain of pathological events, including tauopathy, astrogliosis, accumulation of disease associated microglia (DAM), synaptic and neuronal dysfunction, and eventually dementia. However, the role of adaptive immunity remains unclear. Here we continue our recent discovery that the AD manifestation also depends on B cells. Contrary to the assumption that the adaptive immunity plays a negligible role in AD, we reported that the disease cannot progress if B cells are lost in 3 distinct mice with early onset of AD (EOAD) (Kim et al., Nature Comm, 2021). In the present work, we also demonstrate that manifestation of AD also requires accumulation of CD8+ T cells in the brain. We found that brain parenchyma of mice with EOAD and humans with AD and MCI is significantly increased in CD8+ T cells. By experimenting with 5xFAD and APP/PS1 mice, we provide evidence that their increase is mediated by B cells. We found that B cells preferentially increase unique type of CD8+ T cells in the brain, such as exhausted effector memory, tissue resident CD8+ T cells expressing IFNg and ectonucleotidases involved in adenosine generation, CD39 and CD73. Mechanistically, upon peripheral activation with Ab peptides, CD8+ T cells infiltrate the brain to to affect microglial activity, explaining the significant AD-associated increase of CD8+ T cells complexed with microglia in the brain of mice and humans. As such, transient depletion of CD8+ T cells is sufficient to block AD development in mice, suggesting that the crosstalk between CD8+ T and B cells could be an attractive target for the development of effective therapeutics and safer vaccines to combat this disease in humans. This project is recently submitted for publication (Xin et al., 2023).

根据流行的淀粉样蛋白级联假说，阿尔茨海默病（AD）是由神经毒性淀粉样蛋白Ab-肽聚集体（Ab斑块）在脑中长达数十年的沉积引起的。它导致一系列病理事件，包括tau蛋白病、星形胶质细胞增生、疾病相关小胶质细胞（DAM）的积累、突触和神经元功能障碍，并最终导致痴呆。然而，适应性免疫的作用仍不清楚。在这里，我们继续我们最近的发现，AD的表现也取决于B细胞。 与适应性免疫在AD中起可忽略的作用的假设相反，我们报道了如果B细胞在3只具有早发AD（EOAD）的不同小鼠中丢失，则疾病不能进展（Kim等人，Nature Comm，2021）。在目前的工作中，我们还表明，AD的表现也需要在大脑中积累CD 8 + T细胞。我们发现患有EOAD的小鼠和患有AD和MCI的人类的脑实质中的CD 8 + T细胞显著增加。通过对5xFAD和APP/PS1小鼠的实验，我们提供了它们的增加是由B细胞介导的证据。我们发现，B细胞优先增加脑中独特类型的CD 8 + T细胞，例如耗尽的效应记忆、表达IFNg和参与腺苷生成的外核苷酸酶的组织驻留CD 8 + T细胞、CD 39和CD 73。从机制上讲，在用Ab肽进行外周活化后，CD 8 + T细胞浸润脑以影响小胶质细胞活性，这解释了小鼠和人脑中与小胶质细胞复合的CD 8 + T细胞的显著AD相关增加。因此，CD 8 + T细胞的瞬时消耗足以阻断小鼠中的AD发展，表明CD 8 + T和B细胞之间的串扰可能是开发有效治疗剂和更安全疫苗以对抗人类中该疾病的有吸引力的靶标。该项目最近提交出版（Xin et al.，2023年）。