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The pathways that control the generation of Th1\u2010like Tregs are not well understood. Sphingosine\u20101\u2010phosphate (S1P) signalling molecules are upregulated in Th1\u2010like Tregs, and in\u00a0vivo S1P inhibition with Fingolimod (FTY720) inhibits the expression of genes responsible for Treg plasticity in MS patients. However, the underlying mechanisms are unknown. Here we show that S1P signalling inhibition by FTY720 inhibits the generation of Th1\u2010like Tregs and rescues their suppressive function. These effects are mediated by a decrease in mTORC1 signalling and reversal of the mitochondrial uncoupling that Tregs undergo during their reprogramming into Th1\u2010like Tregs in\u00a0vitro. Finally, these results are validated in in\u00a0vivo\u2010generated Th1\u2010like Tregs, as Tregs from MS patients treated with FTY720 display decreased Th1\u2010like Treg frequency, increased suppressive function and mitochondrial metabolism rebalance. These results highlight the involvement of mitochondrial uncoupling in Treg reprogramming and identify S1P signalling inhibition as a target to suppress the generation of dysfunctional Th1\u2010like Tregs.<\/jats:p>","DOI":"10.1111\/imm.13870","type":"journal-article","created":{"date-parts":[[2024,10,24]],"date-time":"2024-10-24T08:06:43Z","timestamp":1729757203000},"page":"153-166","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["<scp>Sphingosine<\/scp>\u20101\u2010Phosphate Signalling Inhibition Suppresses Th1\u2010Like Treg Generation by Reversing Mitochondrial Uncoupling"],"prefix":"10.1111","volume":"174","author":[{"given":"Rachel","family":"Coulombeau","sequence":"first","affiliation":[{"name":"Department of Infectious Disease, Faculty of Medicine Imperial College London  London 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