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However, the mechanisms that govern their differentiation and function are not completely understood. Herein, we demonstrate a central role for the lipid mediator biosynthetic enzyme 15-lipoxygenase (ALOX15) in regulating key aspects of T<jats:sub>reg<\/jats:sub> biology. Pharmacological inhibition or genetic deletion of ALOX15 in T<jats:sub>regs<\/jats:sub> decreased FOXP3 expression, altered T<jats:sub>reg<\/jats:sub> transcriptional profile and shifted their metabolism. This was linked with an impaired ability of <jats:italic>Alox15<\/jats:italic>-deficient cells to exert their pro-resolving actions, including a decrease in their ability to upregulate macrophage efferocytosis and a downregulation of interferon gamma expression in Th1 cells. Incubation of T<jats:sub>regs<\/jats:sub> with the ALOX15-derived specilized pro-resolving mediators (SPM)s Resolvin (Rv)D3 and RvD5<jats:sub>n-3 DPA<\/jats:sub> rescued FOXP3 expression in cells where ALOX15 activity was inhibited. In vivo, deletion of <jats:italic>Alox15<\/jats:italic> led to increased vascular lipid load and expansion of Th1 cells in mice fed western diet, a phenomenon that was reversed when <jats:italic>Alox15-<\/jats:italic>deficient mice were reconstituted with wild type T<jats:sub>regs<\/jats:sub>. Taken together these findings demonstrate a central role of pro-resolving lipid mediators in governing the differentiation of naive T-cells to T<jats:sub>regs<\/jats:sub>.<\/jats:p>","DOI":"10.1038\/s41418-021-00807-x","type":"journal-article","created":{"date-parts":[[2021,5,27]],"date-time":"2021-05-27T03:34:39Z","timestamp":1622086479000},"page":"3140-3160","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Loss of 15-lipoxygenase disrupts Treg differentiation altering their pro-resolving functions"],"prefix":"10.1038","volume":"28","author":[{"given":"Raquel M.","family":"Marques","sequence":"first","affiliation":[]},{"given":"Maria","family":"Gonzalez-Nunez","sequence":"additional","affiliation":[]},{"given":"Mary E.","family":"Walker","sequence":"additional","affiliation":[]},{"given":"Esteban A.","family":"Gomez","sequence":"additional","affiliation":[]},{"given":"Romain A.","family":"Colas","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3563-376X","authenticated-orcid":false,"given":"Trinidad","family":"Montero-Melendez","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2068-3331","authenticated-orcid":false,"given":"Mauro","family":"Perretti","sequence":"additional","affiliation":[]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6328-3640","authenticated-orcid":false,"given":"Jesmond","family":"Dalli","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2021,5,27]]},"reference":[{"key":"807_CR1","doi-asserted-by":"publisher","first-page":"353ra111","DOI":"10.1126\/scitranslmed.aaf7483","volume":"8","author":"V Chiurchiu","year":"2016","unstructured":"Chiurchiu V, Leuti A, Dalli J, Jacobsson A, Battistini L, Maccarrone M, et al. 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