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

Abstract

Genetic evidence implicates immune dysfunction in Alzheimers 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 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 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. Highlights1) A modular human forebrain organoid platform integrating innate (microglia) and adaptive (CD8+ T cells) immunity recapitulates key features of the human neuroimmune environment 2) Enables mechanistic dissection of multicellular interactions underlying Alzheimers disease pathology 3) Overcomes limitations of traditional animal models by resolving human-specific, cell-type-specific neuroimmune mechanisms 4) Establishes a new approach methodology for studying neuroimmune disorders and advancing drug discovery