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Especially their interplay with encephalitogenic T cells promotes neuroaxonal damage associated with disease progression. In our study, we aimed to explore the potential of siponimod, a sphingosine-1-phosphate modulator approved for the treatment of active SPMS, to inhibit disease-associated T cell-microglia interactions using a chronic murine experimental autoimmune encephalomyelitis (EAE) model of MS. We found that therapeutic siponimod treatment of chronic EAE improved clinical severity accompanied by reduced demyelination and neuroaxonal damage, diminished CNS T cell infiltration and altered proinflammatory microglia responses. This effect was partly attributed to a direct effect on microglia, as siponimod pretreatment inhibited interferon-\u03b3-elicited responses of primary mouse microglia in vitro and limited their ability to induce T cell activation and proliferation in T cell-microglia co-cultures. Additionally, we observed reduced peripheral T cell numbers in our EAE model, with a pronounced shift to immunosenescent and regulatory T cell subsets, a pattern which we similarly detected in a cohort of SPMS patients following siponimod treatment. These findings indicate that siponimod dampens compartmentalized CNS inflammation by disrupting detrimental interactions between T cells and microglia through a dual central and peripheral mechanism of action.<\/jats:p>","DOI":"10.1186\/s40478-025-02136-3","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T12:16:04Z","timestamp":1764591364000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Siponimod inhibits disease-associated microglia-T cell interactions in chronic experimental autoimmune encephalomyelitis"],"prefix":"10.1186","volume":"13","author":[{"given":"Leila","family":"Husseini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anastasia","family":"Geladaris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlene C. 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Blood donors for the analysis of human peripheral blood mononuclear cells and serum biomarkers were enrolled to this study after written informed consent. Ethical approval was obtained from the ethics committee of the University Medical Center G\u00f6ttingen (# 3\/4\/14 and #14\/12\/20).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"M.S.W. received travel funding and\/or speaker honoraria from Biogen-Idec, Merck Serono, Novartis, Roche, TEVA, Bayer, and Genzyme. L.H. received travel funding and speaker honoraria from Novartis. The other authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"247"}}