In a groundbreaking study published recently in Nature Biomedical Engineering, researchers have unveiled novel insights into the mechanisms driving neuronal loss in Huntington’s disease (HD), shedding light on immune interactions previously unappreciated in this devastating neurodegenerative disorder. Using an innovative genetically engineered pig model harboring the mutant human huntingtin gene, scientists have successfully captured the complexity of immune cell infiltration in the central nervous system (CNS) and its direct impact on striatal neuron vulnerability. This represents a substantial leap forward from traditional rodent models, which have long failed to replicate the selective neuronal demise characteristic of HD in humans.
The investigation delved deep into the striatal microenvironment, leveraging cutting-edge single-nucleus transcriptomics alongside spatial transcriptomics to meticulously map cellular populations and their functional states within this disease-relevant brain region. Complementary immunohistochemical analyses and T cell receptor (TCR) sequencing offered a multidimensional view of the intricate cellular interplay underlying HD pathology. This comprehensive approach enabled the identification of a previously unknown interferon-responsive microglial activation state that orchestrates the recruitment of cytotoxic CD8-positive T cells, thereby accelerating neuronal loss through potent effector molecules.
At the heart of these immune-neuronal dynamics lies chemokine ligand eight (CXCL8), which was found to be secreted abundantly by the interferon-activated microglia. CXCL8 functions as a critical chemotactic signal, facilitating the infiltration of cytotoxic T lymphocytes into the striatum, where they unleash perforin and granzyme molecules—potent mediators of cell death—upon vulnerable striatal neurons. This discovery elucidates a pivotal mechanism in HD previously obscured by the limitations of rodent models, whose immune responses and neuronal susceptibilities differ markedly from humans. The pig model’s close anatomical and physiological resemblance to the human brain highlights the profound species-dependent nature of this neuroimmune interaction.
Functional validation experiments underscored the pathogenic significance of the CXCL8-T cell axis. Strategic neutralization of CXCL8 attenuated immune cell infiltration and markedly mitigated neurodegeneration, providing compelling evidence for CXCL8 as a promising therapeutic target. This finding opens an exciting avenue for translational interventions aimed at curbing HD progression by modulating immune mechanisms, expanding beyond the current focus on intrinsic neuronal dysfunction and genetic modifiers.
Huntington’s disease, a fatal hereditary disorder characterized by progressive motor, cognitive, and psychiatric decline, has long challenged researchers to elucidate the precise pathological cascades driving selective neuronal vulnerability. Historically, investigations have centered on neuronal-autonomous mechanisms related to mutant huntingtin toxicity. However, mounting evidence implicates the CNS immune environment as an active participant in disease evolution. The present study decisively positions immune cell infiltration, particularly that mediated by microglia and T cells, as a crucial factor exacerbating neuronal demise in HD.
The use of a genetically engineered pig model carrying an expanded cytosine–adenine–guanine (CAG) repeat in the human huntingtin gene is a particularly salient advance. Pigs share many neuroanatomical and immunological features with humans that are absent in rodents, including similarities in striatal architecture and immune response pathways. This model faithfully recapitulates clinical and neuropathological hallmarks of human HD, thereby enabling the detailed dissection of immune pathways that are otherwise inaccessible. This cross-species relevance strengthens the study’s translational impact for human HD therapy development.
Single-nucleus RNA sequencing (snRNA-seq) was pivotal in revealing cellular heterogeneity within the striatum and in defining microglial states previously masked in bulk tissue analyses. The identification of an interferon-responsive microglial subpopulation emphasizes the nuanced immune landscape within HD-affected brains. These microglia act as inflammatory hubs, expressing elevated levels of CXCL8 that shape the immune milieu toward cytotoxic T cell engagement. This immune axis highlights the paradox of microglial activation: while intended as a protective response, it inadvertently propagates neuroinflammation and neuronal death.
Spatial transcriptomics further contextualized this interaction, confirming the spatial proximity of CXCL8-producing microglia and infiltrating CD8-positive T cells in regions undergoing neuronal loss. This spatial association validates the notion of localized immune cross-talk driving site-specific neurodegeneration in HD. By mapping these cells in situ, the study bridges molecular data with histopathological changes, illuminating a precise neuroimmune interface that can be therapeutically targeted.
T cell receptor sequencing revealed clonally expanded populations of cytotoxic T cells within the striatum, indicating an antigen-driven immune response rather than random infiltration. These CD8-positive T cells express perforin and granzyme, classical cytotoxic effectors capable of inducing apoptosis in target neurons. The study, therefore, supports a model in which mutant huntingtin-expressing neurons – perhaps through stress-induced antigen presentation – become inadvertent targets of immune surveillance, precipitating their demise.
The functional experiments targeting CXCL8 disruption employed neutralizing antibodies that effectively blunted chemotactic signals, reducing cytotoxic T cell presence and resultant neuronal loss. This therapeutic approach not only addresses the inflammatory cascade but also preserves critical neuronal populations that underlie motor and cognitive functions. By preventing the immune-mediated acceleration of neurodegeneration, CXCL8 neutralization offers a potentially disease-modifying strategy distinct from prior symptomatic therapies.
Moreover, the confirmation of this immune mechanism in a large animal model underscores the limitations of rodent-based research in neurodegenerative diseases and emphasizes the need for physiologically relevant models in translational neuroscience. The intricate crosstalk between innate and adaptive immune components in HD may have been overlooked previously due to evolutionary differences, which this pig model elegantly circumvents.
This study also highlights the broader concept that immune-mediated mechanisms of neurodegeneration may be species-specific, implying that clinical trials predicated on rodent data alone may miss critical therapeutic opportunities. Understanding the role of immune cell infiltration and the complex signaling networks that promote neuroinflammation could reshape future drug discovery pipelines focused on HD and other neurodegenerative diseases where inflammation is implicated.
Beyond Huntington’s disease, these findings have impactful implications for the study of neuroimmune interactions in disorders marked by selective neuronal loss. The demonstration of a microglia-T cell axis mediated by CXCL8 draws attention to chemokine signaling pathways as modulators of CNS immune homeostasis and pathology. Targeting these pathways may yield potent immunomodulatory therapies applicable to disorders such as multiple sclerosis, Parkinson’s disease, and amyotrophic lateral sclerosis, where immune cell infiltration contributes to progression.
The integration of multi-omics technologies with histological and functional assays represents a paradigm for future neurodegenerative disease research. This comprehensive approach enables unprecedented resolution of cellular interactions within complex CNS tissues, facilitating the identification of novel therapeutic targets and biomarkers. The study’s methodology sets a new standard for dissecting cellular ecosystems in brain disease.
In conclusion, the discovery of CXCL8-mediated recruitment of cytotoxic CD8-positive T cells by interferon-responsive microglia reveals a species-dependent immune mechanism that accelerates neuronal loss in Huntington’s disease. The genetically engineered pig model provided the physiological context necessary to uncover these intricate neuroimmune dynamics, overcoming limitations of traditional animal models. Neutralizing CXCL8 offers a promising therapeutic avenue, potentially transforming HD treatment strategies by halting immune-driven neurodegeneration. This research marks a pivotal step in understanding and ultimately combatting the complex interplay between the immune system and neurodegeneration.
Subject of Research: Immune cell infiltration and neuroimmune interactions driving neurodegeneration in Huntington’s disease using a genetically engineered pig model.
Article Title: Single-nucleus transcriptomics of an engineered pig model reveals microglia–T cell interactions driving Huntington’s disease neurodegeneration.
Article References:
Li, J., Lin, Y., Gao, J. et al. Single-nucleus transcriptomics of an engineered pig model reveals microglia–T cell interactions driving Huntington’s disease neurodegeneration. Nat. Biomed. Eng (2026). https://doi.org/10.1038/s41551-026-01621-x
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