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

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 +5 more·2023·Nature Neuroscience

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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  • CXCL10 and its receptor CXCR3 play key roles in regulating infiltration of CD8+ T cells into the brain, and infiltrated CD8+ T cells appear to interact with microglia to jointly promote AD neurodegeneration.

    “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]

    The Extended Data (Fig. 7) proposes that infiltrating CD8+ T cells interact with microglia and exacerbate neurodegeneration. The inhibition results show that blocking CXCR3 reduces T-cell infiltration and neuronal damage in AD cultures. The evidence establishes this CXCL10–CXCR3 role in the neuroimmune axis model, not directly in human brains as the citing sentence implies. (LLM, conf=0.84)

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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.

    “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]

  • In an in vitro 3D model recreating interactions between AD cerebral tissue and the immune system, 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.

    “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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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.
Venue
Nature Neuroscience
Published
2023-08-24
Volume
26
Issue
9
Pages
1489-1504
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
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
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
  • Health Sciences › Medicine › Physiology › 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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