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Single-cell transcriptomics reveals species-dependent immune infiltration of T cells in Huntington's disease neurodegeneration

ABSTRACT: Immune infiltration of T cells in the brain has been observed in various pathological conditions, but whether this phenomenon occurs in Huntington disease (HD) remains unknown. To address this question, we conducted an investigation using HD knock-in pigs, which exhibit selective neurodegeneration similar to HD patients. Single-cell transcriptomes identified that glial cells are the most abundant cell type in the human and pig striatum, while neurons outnumber glial cells in the mouse striatum. HD knock-in pigs recapitulate the loss of specific types of striatal neurons (iSPN and dSPN) observed in HD patients, a phenomenon not observed in HD knock-in mice. The increased IFN-activated microglia subgroup in HD knock-in pigs was found to secrete CCL8 chemokines to recruit CD8+ T cells. These T cells release perforin and granzyme, leading to the degeneration of striatal neurons. Although HD-KI mouse striatum does not show elevated CCL8, administration of CCL8 resulted in an increase in CD8+ T cells and a reduction in neuronal cells. These findings suggest that species-dependent abundance of glial cells and the effects of mutant huntingtin on glial cells contribute to microglia-driven immune infiltration of CD8+ T cells, ultimately playing a critical role in the selective neurodegeneration in HD.

ORGANISM(S): Sus scrofa

PROVIDER: GSE254278 | GEO | 2025/11/20

REPOSITORIES: GEO

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