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While the related factors Helios and Eos have defined roles in regulatory T cells (Treg), a role for Ikaros has not been established. To determine the function of Ikaros in the Treg lineage, we generated mice with Treg-specific deletion of the Ikaros gene (\n                    <jats:italic>Ikzf1<\/jats:italic>\n                    ). We find that Ikaros cooperates with Foxp3 to establish a major portion of the Treg epigenome and transcriptome. Ikaros-deficient Treg exhibit Th1-like gene expression with abnormal production of IL-2, IFNg, TNFa, and factors involved in Wnt and Notch signaling. While\n                    <jats:italic>Ikzf1<\/jats:italic>\n                    -Treg-cko mice do not develop spontaneous autoimmunity, Ikaros-deficient Treg are unable to control conventional T cell-mediated immune pathology in response to TCR and inflammatory stimuli in models of IBD and organ transplantation. These studies establish Ikaros as a core factor required in Treg for tolerance and the control of inflammatory immune responses.\n                  <\/jats:p>","DOI":"10.7554\/elife.91392","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T14:39:28Z","timestamp":1699886368000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.91392","source":"Crossref","is-referenced-by-count":5,"title":["Foxp3 depends on Ikaros for control of regulatory T cell gene expression and function"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2652-9992","authenticated-orcid":true,"given":"Rajan M","family":"Thomas","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01z7r7q48","id-type":"ROR","asserted-by":"publisher"}],"name":"Center for Spatial and Functional Genomics, The Children\u2019s Hospital of Philadelphia","place":["Philadelphia, United 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