{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T23:43:55Z","timestamp":1792712635796,"version":"4.5.0"},"reference-count":19,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    Epstein-Barr virus-induced gene 3(EBI3) is conventionally viewed as a subunit of IL-27 and IL-35, yet the function of uncomplexed \u201cfree\u201d EBI3 is unknown. We show that free EBI3 is an autonomous immunosuppressive cytokine that acts via a gp130\/WSX-1\/STAT3 axis and epigenetic reprogramming. A free-EBI3-specific sandwich ELISA revealed 23.3 \u00b1 2.2 ng\/mL in healthy human sera and equivalent levels in mice; no cross-reactivity with IL-27\/IL-35 was observed. Serum free EBI3 was reduced in rheumatoid arthritis(RA; 12.4 \u00b1 1.4 ng\/mL) and multiple sclerosis (MS; 14.6 \u00b1 1.4 ng\/mL; both p&amp;lt; 0.001) and inversely correlated with disease activity(RA-DAS28-ESR r=-0.67; MS-EDSS r=-0.61). Baseline&amp;lt;15 ng\/mL predicted higher flare risk(RA HR = 2.8;MS HR = 3.2;p&amp;lt;0.01). Recombinant free EBI3 activated STAT3 exclusively(EC50\u224816 nM), suppressed T-cell proliferation (-40%),IFN-y(-45%) and IL-17(-60%),and drove M2 macrophage polarization (+2.7-fold;p&amp;lt;0.001).Epigenetically,it reduced H3K4me3 at Ifng\/Il4 promoters, induced Il10\/Tgfb hypomethylation(-35%\/-28%), and remodeled 1,021 chromatin-accessible STAT3\/NF-kB sites. EBI3\n                    <jats:sup>-\/-<\/jats:sup>\n                    mice developed spontaneous colitis and severe EAE; daily free EBI3(1 mg\/kg) reversed pathology, whereas IL-27\/IL-35 did not. Tissue-targeted delivery(liposomes or nanoparticles) outperformed systemic therapy.\n                    <jats:italic>Ex-vivo<\/jats:italic>\n                    free EBI3 normalized RA\/MS patient PBMCs(proliferation-50%; IL-17-52%; p&amp;lt; 0.001). Thus, free EBI3 is a distinct cytokine whose gp130\/WSX-1 axis constitutes a biomarker and therapeutic target for inflammatory diseases.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2026.1858675","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T04:25:14Z","timestamp":1785126314000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Free Epstein-Barr virus-induced gene 3 functions as an autonomous immunosuppressive cytokine to maintain immune tolerance"],"prefix":"10.3389","volume":"17","author":[{"given":"Beiping","family":"Miao","sequence":"first","affiliation":[{"name":"Department of Otolaryngology, Head & Neck Surgery, Shenzhen Second People\u2019s Hospital","place":["Shenzhen, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruishi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Shenzhen Second 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