{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,11]],"date-time":"2025-11-11T22:38:03Z","timestamp":1762900683050,"version":"3.41.2"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T00:00:00Z","timestamp":1738713600000},"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:sec><jats:title>Background<\/jats:title><jats:p>Umbilical cord blood (UCB)-derived CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>CD127<jats:sup>low<\/jats:sup> regulatory T cells (Tregs) can decrease albuminuria and anti-dsDNA IgG in systemic lupus erythematosus (SLE). Ruxolitinib, a JAK\/STAT inhibitor, has been shown to improve cutaneous manifestations of SLE. We hypothesize that the addition of ruxolitinib to UCB-Tregs may improve SLE outcomes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>In vitro<\/jats:italic> cell suppression, phenotype change, IL-10 secretion, and cytokine levels in coculture supernatants were determined to quantify the impact of adding ruxolitinib to UCB-Tregs. A xenogeneic SLE model was utilized to study their <jats:italic>in vivo<\/jats:italic> combination.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In a dose-dependent manner, ruxolitinib addition synergizes with UCB-Tregs to suppress SLE-PBMC proliferation, inhibit CD8<jats:sup>+<\/jats:sup> T cells, and reduce phosphorylation of STAT3\/STAT5\/AKT in CD8<jats:sup>+<\/jats:sup> T cells. UCB-Treg and ruxolitinib combination also downregulates the soluble form of inflammatory cytokines including IFN-\u03b3, IP-10, TNF-\u03b1, IL-6, sCD40L, IL-17A, IL-17F, IL-1\u03b1, and LIF in cocultures. The addition of ruxolitinib increases UCB-Treg cell persistence in peripheral blood <jats:italic>in vivo<\/jats:italic> and decreases the soluble form of human inflammatory cytokines including IFN-\u03b3, TNF-\u03b1, and sCD40L in plasma along with improvement of skin lesions in SLE xenografts. Compared to control, significantly lesser CD3<jats:sup>+<\/jats:sup>, CD4<jats:sup>+<\/jats:sup>, CD8<jats:sup>+<\/jats:sup>, and Ki-67<jats:sup>+<\/jats:sup> infiltrates are observed in the lung and kidney of UCB-Tregs and\/or ruxolitinib recipients. No added benefit of addition of ruxolitinib is observed on the significant improvement in the urine albumin\/creatinine ratio and the anti-dsDNA IgG levels induced by UCB-Tregs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our results demonstrate that the addition of ruxolitinib to UCB-Tregs increases UCB-Tregs suppressor function and their persistence <jats:italic>in vivo<\/jats:italic>, downregulates systemic inflammation, and controls cutaneous SLE but does not add to UCB-Treg-mediated improvement in renal manifestations.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1449693","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T07:39:33Z","timestamp":1738741173000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Ruxolitinib synergizes with regulatory T cells to improve inflammation but has no added benefits in decreasing albuminuria in 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