{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T22:38:05Z","timestamp":1776724685585,"version":"3.51.2"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T00:00:00Z","timestamp":1621382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100008392","name":"Sundhed og Sygdom, Det Frie Forskningsr\u00e5d","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008392","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The active form of vitamin D, 1,25-dihydroxyvitamin D<jats:sub>3<\/jats:sub> (1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub>), mediates its immunomodulatory effects by binding to the vitamin D receptor (VDR). Here, we describe a new point mutation in the DNA-binding domain of the VDR and its consequences for 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> signaling in T cells from heterozygous and homozygous carriers of the mutation. The mutation did not affect the overall structure or the ability of the VDR to bind 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> and the retinoid X receptor. However, the subcellular localization of the VDR was strongly affected and the transcriptional activity was abolished by the mutation. In heterozygous carriers of the mutation, 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub>-induced gene regulation was reduced by ~ 50% indicating that the expression level of wild-type VDR determines 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> responsiveness in T cells. We show that vitamin D-mediated suppression of vitamin A-induced gene regulation depends on an intact ability of the VDR to bind DNA. Furthermore, we demonstrate that vitamin A inhibits 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub>-induced translocation of the VDR to the nucleus and 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub>-induced up-regulation of CYP24A1. Taken together, this study unravels novel aspects of vitamin D signaling and function of the VDR in human T cells.<\/jats:p>","DOI":"10.3389\/fimmu.2021.684015","type":"journal-article","created":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T05:37:07Z","timestamp":1621402627000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":14,"title":["Impaired Vitamin D Signaling in T Cells From a Family With Hereditary Vitamin D Resistant Rickets"],"prefix":"10.3389","volume":"12","author":[{"given":"Fatima A. 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