An integrated human forebrain organoid reveals microglia-mediated CD8⁺ T cell recruitment and neuroimmune dysfunction in Alzheimer's disease pathology

Genetic evidence implicates immune dysfunction in Alzheimers disease (AD), yet human-specific neuroimmune mechanisms remain poorly defined. Here, we establish a modular human forebrain organoid platform that systematically integrates iPSC-derived microglia and CD8+ T cells to reconstitute multicellular Alzheimers disease 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-{beta} clearance and neuronal maturation but also drive inflammatory activation and recruit CD8+ T cells through CCL4/5-CXCL10 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. HighlightsO_LIA modular human forebrain organoid platform integrating innate (microglia) and adaptive (CD8+ T cells) immunity recapitulates key features of the human neuroimmune environment C_LIO_LIEnables mechanistic dissection of multicellular interactions underlying Alzheimers disease pathology C_LIO_LIOvercomes limitations of traditional animal models by resolving human-specific, cell-type-specific neuroimmune mechanisms C_LIO_LIEstablishes a new approach methodology for studying neuroimmune disorders and advancing drug discovery C_LI