CX3CL1 (fractalkine)–CX3CR1 interface drives CD8⁺ T cell–induced neurodegeneration in human brain organoids
4 affiliations
- 1Department of Genetics, Interdepartmental Neuroscience Program, Yale Stem Cell Center, Yale Child Study Center, Wu Tsai Institute, Yale School of Medicine, New Haven, CT 06520
- 2Department of Internal Medicine, Section of Rheumatology, Allergy & Immunology, Yale School of Medicine, New Haven, CT 06520
- 3College of Pharmacy, Sookmyung Women’s University, Seoul 04310, Republic of Korea
- 4Department of Pathology, Yale School of Medicine, New Haven, CT 06520
Abstract
Immune–neuron interactions play a critical role in neuroinflammatory and neurodegenerative diseases, such as Alzheimer’s disease (AD), but how CD8⁺ T cells contribute to brain pathology remains poorly understood. Amyloid-β (Aβ), a hallmark of AD, is known to trigger neuronal stress and inflammation. Here, we established a human cortical organoid (hCO) model to investigate CD8⁺ T cell responses to Aβ-induced neurodegenerative stress. Aβ exposure increased neuronal expression of CX3CL1 (fractalkine), which engages its receptor CX3CR1 on CD8⁺ T cells. Transwell migration assays showed enhanced recruitment of CX3CR1⁺ CD8⁺ T cells toward Aβ-treated hCOs. In parallel, Aβ upregulated IL-15 expression, a cytokine that supports CD8⁺ T cell activation. The infiltration of CD8⁺ T cells led to neuronal injury, marked by MAP2 loss and cleaved Caspase-3 activation, accompanied by an increase in gene signatures for cell death and inflammation. Exposure to the conditioned medium of activated CX3CR1high CD8⁺ T cell recapitulated this damage, and the neutralization of CD8+ T cell cytokines and cytotoxic molecules rescued the phenotype. These findings identify the CX3CL1–CX3CR1 axis and CD8⁺ T cell effector programs as drivers of neurotoxicity and establish brain organoids as a platform to study immune-driven neurodegeneration.
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BibTeX
@article{yang2026cx3cl1,
title = {{CX3CL1 (fractalkine)–CX3CR1 interface drives CD8⁺ T cell–induced neurodegeneration in human brain organoids}},
author = {Woo Sub Yang and Min Sun Shin and Mu Seog Choe and Ferdi Ridvan Kiral and Jumee Kim and Hong-Jai Park and Mario Felix and Lais Osmani and In-Hyun Park and Insoo Kang},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = oct,
doi = {10.1073/pnas.2605209123},
url = {https://doi.org/10.1073/pnas.2605209123},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - CX3CL1 (fractalkine)–CX3CR1 interface drives CD8⁺ T cell–induced neurodegeneration in human brain organoids
AU - Woo Sub Yang
AU - Min Sun Shin
AU - Mu Seog Choe
AU - Ferdi Ridvan Kiral
AU - Jumee Kim
AU - Hong-Jai Park
AU - Mario Felix
AU - Lais Osmani
AU - In-Hyun Park
AU - Insoo Kang
PY - 2026
DA - 2026/10/20
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2605209123
UR - https://doi.org/10.1073/pnas.2605209123
AB - Immune–neuron interactions play a critical role in neuroinflammatory and neurodegenerative diseases, such as Alzheimer’s disease (AD), but how CD8⁺ T cells contribute to brain pathology remains poorly understood. Amyloid-β (Aβ), a hallmark of AD, is known to trigger neuronal stress and inflammation. Here, we established a human cortical organoid (hCO) model to investigate CD8⁺ T cell responses to Aβ-induced neurodegenerative stress. Aβ exposure increased neuronal expression of CX3CL1 (fractalkine), which engages its receptor CX3CR1 on CD8⁺ T cells. Transwell migration assays showed enhanced recruitment of CX3CR1⁺ CD8⁺ T cells toward Aβ-treated hCOs. In parallel, Aβ upregulated IL-15 expression, a cytokine that supports CD8⁺ T cell activation. The infiltration of CD8⁺ T cells led to neuronal injury, marked by MAP2 loss and cleaved Caspase-3 activation, accompanied by an increase in gene signatures for cell death and inflammation. Exposure to the conditioned medium of activated CX3CR1high CD8⁺ T cell recapitulated this damage, and the neutralization of CD8+ T cell cytokines and cytotoxic molecules rescued the phenotype. These findings identify the CX3CL1–CX3CR1 axis and CD8⁺ T cell effector programs as drivers of neurotoxicity and establish brain organoids as a platform to study immune-driven neurodegeneration.
SN - 0027-8424
SN - 1091-6490
ER -