{"doi":"10.1101/2024.07.09.602661","title":"Interleukin-33 from oligodendrocytes sustains effector differentiation of tissue-resident CD8+ T cells and is a druggable target in CNS autoimmune disease","abstract":"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-1 low 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.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":500887,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9572,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":831074,"name":"Nicolas Pagé","orcid":"0000-0002-5845-6831","position":1,"is_corresponding":false},{"id":1350343,"name":"Bogna Klimek","orcid":"0000-0002-2089-2048","position":2,"is_corresponding":false},{"id":1350591,"name":"Margot Piccinno","orcid":null,"position":3,"is_corresponding":false},{"id":1350344,"name":"Giovanni Di Liberto","orcid":"0000-0001-6788-0215","position":4,"is_corresponding":false},{"id":1350345,"name":"Sylvain Lemeille","orcid":"0000-0003-4197-6483","position":5,"is_corresponding":false},{"id":1231615,"name":"Mario Kreutzfeldt","orcid":"0000-0003-0335-2733","position":6,"is_corresponding":false},{"id":1232160,"name":"Anna Lena Kastner","orcid":null,"position":7,"is_corresponding":false},{"id":1231613,"name":"Yusuf I. Ertuna","orcid":"0000-0002-7714-0605","position":8,"is_corresponding":false},{"id":1350346,"name":"Ilena Vincenti","orcid":"0000-0003-1061-6071","position":9,"is_corresponding":false},{"id":1231614,"name":"Ingrid Wagner","orcid":"0000-0003-4437-9799","position":10,"is_corresponding":false},{"id":1231616,"name":"Daniel D. Pinschewer","orcid":"0000-0002-1594-3189","position":11,"is_corresponding":false},{"id":644577,"name":"Doron Merkler","orcid":"0000-0002-0247-2007","position":12,"is_corresponding":false},{"id":1350590,"name":"Nicolas Fonta","orcid":null,"position":0,"is_corresponding":true}],"reference_count":56,"raw_metadata":null,"created_at":"2026-07-19T02:10:12.068207Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}