Single-nucleus transcriptomics of an engineered pig model reveals microglia-T cell interactions driving Huntington's disease neurodegeneration.

Immune cell infiltration into the central nervous system is increasingly recognized as a driver of neurodegeneration, yet its role in Huntington's disease remains unresolved. Addressing this question requires models that replicate the selective vulnerability of striatal neurons observed in patients, a challenge unmet by rodent systems. Here we use a previously established and genetically engineered pig model carrying the human huntingtin mutation with an expanded cytosine-adenine-guanine repeat, enabling investigation of immune-neural interactions in a physiologically relevant context. Using single-nucleus and spatial transcriptomics, integrated with immunohistochemistry and T cell receptor sequencing, we constructed a cellular map of the striatum. We identified an interferon-responsive microglial state that secretes chemokine ligand eight, recruiting cytotoxic CD8-positive T cells that release perforin and granzyme, thereby accelerating neuronal loss. Functional experiments confirmed the pathogenic role of chemokine ligand eight and demonstrated that its neutralization mitigates neurodegeneration. These findings uncover a species-dependent immune mechanism in Huntington's disease and nominate chemokine ligand eight-mediated T cell infiltration as a therapeutic target.