Cited by 217Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsNeurological Disease Mechanisms and Treatments

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Infiltrating CD8+ T cells exacerbate Alzheimer’s disease pathology in a 3D human neuroimmune axis model

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Jorfi, Mehdi, Park, Joseph, Hall, Clare K., Lin, Chih-Chung Jerry, Chen, Meng, von Maydell, Djuna, Kruskop, Jane M., Kang, Byunghoon, Choi, Younjung, Prokopenko, Dmitry, Irimia, Daniel, Kim, Doo Yeon, Tanzi, Rudolph E.·2023·Nature Neuroscience

DOI 10.1038/s41593-023-01415-3PMC PMC11184920

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Abstract

Brain infiltration of peripheral immune cells and their interactions with brain-resident cells may contribute to Alzheimer's disease (AD) pathology. To examine these interactions, in the present study we developed a three-dimensional human neuroimmune axis model comprising stem cell-derived neurons, astrocytes and microglia, together with peripheral immune cells. We observed an increase in the number of T cells (but not B cells) and monocytes selectively infiltrating into AD relative to control cultures. Infiltration of CD8+ T cells into AD cultures led to increased microglial activation, neuroinflammation and neurodegeneration. Using single-cell RNA-sequencing, we identified that infiltration of T cells into AD cultures led to induction of interferon-γ and neuroinflammatory pathways in glial cells. We found key roles for the C-X-C motif chemokine ligand 10 (CXCL10) and its receptor, CXCR3, in regulating T cell infiltration and neuronal damage in AD cultures. This human neuroimmune axis model is a useful tool to study the effects of peripheral immune cells in brain disease.

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Authors: Jorfi, M., Park, J., Hall, C. K., Lin, C.-C. J., Chen, M., von Maydell, D., Kruskop, J. M., Kang, B., Choi, Y., Prokopenko, D., Irimia, D., Kim, D. Y., & Tanzi, R. E.
Affiliations: Harvard University (US)
Massachusetts General Hospital (US)
Corresponding author: Jorfi, Mehdi
Kim, Doo Yeon
Tanzi, Rudolph E.
ORCID: Jorfi, Mehdi
Park, Joseph
Lin, Chih-Chung Jerry
Prokopenko, Dmitry
Irimia, Daniel
Kim, Doo Yeon
Tanzi, Rudolph E.
Venue: Nature Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2023-08-24
Volume: 26
Issue: 9
Pages: 1489-1504
ISSN: 1097-6256 (ISSN-L)
1546-1726
DOI: 10.1038/s41593-023-01415-3
PMC: PMC11184920
OpenAlex: W4386134158
Cited by: 214
References: 61
Citations by year: 2026: 68 · 2025: 65 · 2024: 74 · 2023: 7
FWCI: 22.37
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: Nature Neuroscience (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: Cure Alzheimer’s Fund
JPB Foundation
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
Keywords: Alzheimer's disease, CD8+ T cells, T cell infiltration, neuroinflammation, microglial activation, neurodegeneration, CXCL10, CXCR3, interferon-gamma, peripheral immune cells, stem cell-derived neurons, astrocytes, monocytes
MeSH terms: Alzheimer Disease, Humans, Neuroglia, Neurons, Neuroimmunomodulation, CD8-Positive T-Lymphocytes

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Infiltrating CD8+ T cells exacerbate Alzheimer’s disease pathology in a 3D human neuroimmune axis model

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