CX3CL1 (fractalkine)-CX3CR1 interface drives CD8⁺ T cell-induced neurodegeneration in human brain organoids.
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 neu
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 CX3CR1 high 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.
