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These receptors share the retinoid X receptor (RXR) co\u2010factor for transcriptional regulation. We investigated the effects of active vitamin D\n                    <jats:sub>3<\/jats:sub>\n                    (1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D\n                    <jats:sub>3<\/jats:sub>\n                    ) and 9\u2010\n                    <jats:italic>cis<\/jats:italic>\n                    retinoic acid (9cRA) on T helper (T\n                    <jats:sub>H<\/jats:sub>\n                    )1 and T\n                    <jats:sub>H<\/jats:sub>\n                    2 cytokines and transcription factors in primary human blood\u2010derived CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cells. We aimed to address the discrepancies in this field, particularly regarding the effects of 9cRA and the vitamins in combination. 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D\n                    <jats:sub>3<\/jats:sub>\n                    upregulated IL\u201013 and suppressed IFN\u03b3, while 9cRA had the opposite effects. This was largely independent of a T\n                    <jats:sub>H<\/jats:sub>\n                    1\/T\n                    <jats:sub>H<\/jats:sub>\n                    2 phenotype shift. Combined vitamin supplementation produced intermediate cytokine levels, not only through transcriptional regulation by VDR\u2010RXR and RAR\u2010RXR but also through 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D\n                    <jats:sub>3<\/jats:sub>\n                    counteracting the effects of 9cRA on solely 9cRA\u2010responsive genes. Similar results were observed in hereditary vitamin D\u2010resistant rickets (HVDRR) patient T cells, where VDR cannot bind to DNA, indicating that RXR binding to either receptor can limit the other's activity. Additionally, we observed downregulated RAR upon 9cRA supplementation and its re\u2010localization out of the nucleus upon 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D\n                    <jats:sub>3<\/jats:sub>\n                    supplementation, suggesting a mechanism of indirect regulation by VDR. VDR protein levels were also upregulated upon 9cRA supplementation, suggesting a novel negative feedback mechanism of 9cRA transcriptional activity, whereby 9cRA promotes its own competitor. This study sets the stage for future research into the combined immunomodulatory mechanisms of 1,25(OH)\n                    <jats:sub>2<\/jats:sub>\n                    D\n                    <jats:sub>3<\/jats:sub>\n                    and 9cRA, involving both direct transcriptional regulation and indirect regulation via RXR competitive binding.\n                  <\/jats:p>","DOI":"10.1111\/sji.13429","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T23:54:37Z","timestamp":1737071677000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Vitamin\n                    <scp>\n                      D\n                      <sub>3<\/sub>\n                    <\/scp>\n                    \u2013\n                    <scp>VDR<\/scp>\n                    and vitamin A\u2010\n                    <scp>RAR<\/scp>\n                    affect\n                    <scp>IL<\/scp>\n                    \u201013 and\n                    <scp>IFN\u03b3<\/scp>\n                    secretion from human\n                    <scp>CD4<\/scp>\n                    <sup>+<\/sup>\n                    T cells directly and indirectly via competition for their shared co\u2010receptor\n                    <scp>RXR<\/scp>"],"prefix":"10.1111","volume":"101","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-7935-1816","authenticated-orcid":false,"given":"Tiana","family":"Stanisic","sequence":"first","affiliation":[{"name":"LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-3695-8709","authenticated-orcid":false,"given":"Emma Uttrup","family":"Ewing","sequence":"additional","affiliation":[{"name":"LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4395-1272","authenticated-orcid":false,"given":"Alma","family":"Lindell","sequence":"additional","affiliation":[{"name":"LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3016-1652","authenticated-orcid":false,"given":"Fatima","family":"Al\u2010Jaberi","sequence":"additional","affiliation":[{"name":"LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3496-9333","authenticated-orcid":false,"given":"Martin","family":"Kongsbak\u2010Wismann","sequence":"additional","affiliation":[{"name":"LEO Foundation Skin Immunology Research Center, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences University of Copenhagen  Copenhagen 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