Oligodendrocyte-derived IL-33 regulates self-reactive CD8+ T cells in CNS autoimmunity
IL-33 plays a critical role in shaping the transcriptional landscape of autoreactive CD8 + T cells during CNS autoimmunity. Seurat clustering of cells identifying 10 clusters ©Fonta/UNIGE.
SUMMARY
In chronic inflammatory disorders of the central nervous system (CNS), tissue-resident self-reactive T cells perpetuate disease. The specific tissue factors governing the persistence and continuous differentiation of these cells remain undefined but could represent attractive therapeutic targets. In a model of chronic CNS autoimmunity, we find that oligodendrocyte-derived IL-33, an alarmin, is key for locally regulating the pathogenicity of self-reactive CD8+ T cells. The selective ablation of IL-33 from neo–self-antigen–expressing oligodendrocytes mitigates CNS disease. In this context, fewer self-reactive CD8+ T cells persist in the inflamed CNS, and the remaining cells are impaired in generating TCF-1low effector cells. Importantly, interventional IL-33 blockade by locally administered somatic gene therapy reduces T cell infiltrates and improves the disease course. This study identifies oligodendrocyte-derived IL-33 as a druggable tissue factor regulating the differentiation and survival of self-reactive CD8+ T cells in the inflamed CNS. This finding introduces tissue factors as a novel category of immune targets for treating chronic CNS autoimmune diseases.
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Why is this important?
Chronic autoimmune diseases like multiple sclerosis involve the immune system attacking the brain's own cells. This study reveals that oligodendrocytes, cells responsible for producing myelin in the central nervous system, release a molecule called IL-33. IL-33 promotes the survival and activity of self-reactive CD8+ T cells, which contribute to ongoing inflammation and tissue damage. By blocking IL-33, researchers observed a reduction in these harmful T cells and an improvement in disease symptoms in a mouse model. This finding suggests that targeting IL-33 could be a promising therapeutic strategy for treating chronic CNS autoimmune conditions.
12 May 2025