An integrated human forebrain organoid reveals microglia-mediated CD8⁺ T cell recruitment and neuroimmune dysfunction in Alzheimer's disease pathology.
- 1Institute of Biopharmaceutical and Health Engineering (iBHE), Tsinghua Shenzhen International Graduate School (SIGS), Tsinghua University, Shenzhen, China.
- 2Key Laboratory of Active Proteins and Peptides Green Biomanufacturing of Guangdong Higher Education Institutes, Tsinghua Shenzhen International Graduate School, Shenzhen, China.
- 3Key Laboratory of Industrial Biocatalysis, Ministry of Education, Tsinghua University, Beijing, China.
Abstract
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.
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BibTeX
@article{feng2026integrated,
title = {{An integrated human forebrain organoid reveals microglia-mediated CD8⁺ T cell recruitment and neuroimmune dysfunction in Alzheimer's disease pathology.}},
author = {Yilin Feng and Feifei Yu and Jiyuan Tang and Honghui Zheng and Zitian Wang and Shaohua Ma},
journal = {ELife},
year = {2026},
month = oct,
doi = {10.7554/elife.111730},
url = {https://europepmc.org/article/MED/42899469},
note = {CC BY},
}
RIS
TY - JOUR
TI - An integrated human forebrain organoid reveals microglia-mediated CD8⁺ T cell recruitment and neuroimmune dysfunction in Alzheimer's disease pathology.
AU - Yilin Feng
AU - Feifei Yu
AU - Jiyuan Tang
AU - Honghui Zheng
AU - Zitian Wang
AU - Shaohua Ma
PY - 2026
DA - 2026/10/20
JO - ELife
DO - 10.7554/elife.111730
UR - https://europepmc.org/article/MED/42899469
AB - 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.
SN - 2050-084X
ER -