Interleukin-33 from oligodendrocytes sustains effector differentiation of tissue-resident CD8+ T cells and is a druggable target in CNS autoimmune disease

Abstract 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 interleukin-33 (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 largely locked into a stem-like precursor program, failing to form TCF-1low effector progeny. Importantly, interventional IL-33 blockade by locally administered somatic gene therapy reduces T cell infiltrates and improves the disease course. Our study identifies oligodendrocyte-derived IL-33 as a druggable tissue factor regulating the differentiation and survival of self-reactive CD8+ T cell in the inflamed CNS. This finding introduces tissue factors as a novel category of immune targets for treating chronic CNS autoimmune diseases. Competing Interest Statement D.M., D.D.P., M.K. and N.P. are listed as inventors on a patent related to this work: PCT/EP2015/076458, Tri-segmented arenaviruses as vaccine vectors. D.D.P. is a founder, shareholder and advisor to Hookipa Pharma Inc. commercializing arenavirus vectors. The remaining authors declare that they have no competing interests. Data availability Data are available in the article and Supplementary data file or from the corresponding author upon reasonable request. The raw and processed RNA-seq data have been deposited to the Gene Expression Omnibus (GEO) under accession numbers GEO: GSExxxx.