整合小胶质细胞与CD8+ T细胞的人前脑类器官揭示阿尔茨海默病神经免疫失调
An integrated human forebrain organoid reveals microglia-mediated CD8+ T cell recruitment and neuroimmune dysfunction in Alzheimer’s disease pathology
研究团队建立了一个模块化人前脑类器官平台，将人诱导多能干细胞来源的小胶质细胞和CD8+ T细胞系统整合进去，以重建阿尔茨海默病的多细胞病理。该平台可在人体相关背景下同时考察固有免疫和适应性免疫组分。研究发现，小胶质细胞既介导淀粉样蛋白β清除和神经元成熟，也驱动炎症激活，并通过CCL4/5信号经CCR1/5和CXCR3招募CD8+ T细胞，形成神经炎症反馈环路。药理学靶向CCR5或CXCR3可阻断T细胞招募，并以依赖小胶质细胞的方式调节自噬。作者认为，该模块化类器官平台可用于解析神经元与免疫细胞互作，并支持在人类神经炎症疾病模型中开展细胞类型特异的治疗筛选。
来源：eLife · doi.org
Genetic evidence implicates immune dysfunction in Alzheimer’s disease (AD), yet the neuroimmune mechanisms operating in human tissue remain poorly defined. Here, we establish a modular human forebrain organoid platform that systematically integrates human induced pluripotent stem cell-derived microglia and CD8 + T cells to reconstitute multicellular AD pathology. This system enables functional interrogation of both innate and adaptive immune components in a human-relevant context. Using this platform, we demonstrate that microglia mediate amyloid-β clearance and neuronal maturation but also drive inflammatory activation and recruit CD8 + T cells through CCL4/5 signaling via CCR1/5 and CXCR3, establishing a neuroinflammatory feedback loop. Pharmacological targeting of CCR5 or CXCR3 blocks T cell recruitment and modulates autophagy in a microglia-dependent manner. This modular organoid platform provides a versatile tool for dissecting neuron–immune interactions and enables cell-type-specific therapeutic screening in human neuroinflammatory disease models.