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Oligodendrocyte-derived IL-33 regulates self-reactive CD8+ T cells in CNS autoimmunity

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Title: Oligodendrocyte-derived IL-33 regulates self-reactive CD8+ T cells in CNS autoimmunity
Authors: Fonta, Nicolas, Page, Nicolas, Klimek, Bogna, Piccinno, Margot, Di Liberto, Giovanni, Lemeille, Sylvain, Kreutzfeldt, Mario, Kastner, Anna Lena, Ertuna, Yusuf I, Vincenti, Ilena, Wagner, Ingrid, Pinschewer, Daniel D, Merkler, Doron
Source: J Exp Med
Publisher Information: Rockefeller University Press, 2025.
Publication Year: 2025
Subject Terms: Central Nervous System, Encephalomyelitis, Autoimmune, Experimental, Oligodendroglia / immunology, Central Nervous System / pathology, Brief Definitive Report, Autoimmunity, Cell Differentiation, Encephalomyelitis, Autoimmune, Experimental / immunology, 616.07, CD8-Positive T-Lymphocytes, Interleukin-33, Cell Differentiation / immunology, Encephalomyelitis, Autoimmune, Experimental / pathology, Mice, Inbred C57BL, Oligodendroglia, Mice, CD8-Positive T-Lymphocytes / immunology, Interleukin-33 / genetics, Interleukin-33 / immunology, Oligodendroglia / metabolism, Interleukin-33 / metabolism, Animals, Autoimmunity / immunology, Central Nervous System / immunology
Description: 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. Our 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.
Document Type: Article
Other literature type
File Description: application/pdf
Language: English
ISSN: 1540-9538
0022-1007
DOI: 10.1084/jem.20241188
Access URL: https://pubmed.ncbi.nlm.nih.gov/40227193
Rights: CC BY
URL: http://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at http://creativecommons.org/licenses/by/4.0/).
Accession Number: edsair.doi.dedup.....2b25522c92684c4a4f1ab89e301a9512
Database: OpenAIRE
Description
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 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. Our 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.
ISSN:15409538
00221007
DOI:10.1084/jem.20241188