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Infiltrating CD8+ T cells exacerbate Alzheimer’s disease pathology in a 3D human neuroimmune axis model
Open accessAbstract
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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“The study found that C-X-C motif chemokine ligand 10 (CXCL10) and its receptor CXCR3 play key roles in regulating the infiltration of CD8+ T cells into the brain, and the infiltrated CD8+ T cells appear to interact with microglia to jointly promote AD’s neurodegeneration.257”
From Recent advances in Alzheimer's disease: Mechanisms, clinical trials and new drug development strategies. (2024) · cites this paper as [257]
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“T-lymphocyte infiltration into the brain has been previously reported in AD patients and has been associated with impaired cognition (Gate et al., 2020; Jorfi et al., 2023).”
From Cholesterol 25-hydroxylase mediates neuroinflammation and neurodegeneration in a mouse model of tauopathy (2024) · cites this paper as Jorfi et al., 2023
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“Although B cells infiltrated the in vitro 3D model of AD brain in very low numbers, they significantly elevated protein levels of complement proteins and chemokines compared to cultures lacking B cells [83].”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [83]
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“The results revealed that B cells do not preferentially infiltrate AD 3D cultures compared to control cultures. Instead, B cell infiltration was significantly reduced, particularly in the presence of microglia [83].”
From Is there a role for B cells in Alzheimer's disease? (2026) · cites this paper as [83]
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Metadata
- 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
- Venue
- Nature Neuroscience
- Published
- 2023-08-24
- Volume
- 26
- Issue
- 9
- Pages
- 1489-1504
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- 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
- 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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