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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2026年2月24日

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  • Jiawei Li,
  • Yingqi Lin,
  • Jiale Gao,
  • Fan Yang,
  • Caijuan Li,
  • Yizhi Chen,
  • Chunhui Huang,
  • Xichen Song,
  • Zebu Song,
  • Jianhao Wu,
  • Jiaxi Wu,
  • Wei Wang,
  • Junzhu Song,
  • Chunxiang Shi,
  • Guangchao Cao,
  • Yan Xu,
  • Yankuo Sun,
  • Zhuchi Tu,
  • Liangxue Lai,
  • Shihua Li,
  • Xiao-Jiang Li,
  • Sen Yan

摘要

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.