Impaired Vitamin D Signaling in T Cells From a Family With Hereditary Vitamin D Resistant Rickets

• Published in: Frontiers in immunology 2021-05, Vol.12, p.684015-684015
• Main Authors: Al-Jaberi, Fatima A. H., Kongsbak-Wismann, Martin, Aguayo-Orozco, Alejandro, Krogh, Nicolai, Buus, Terkild B., Lopez, Daniel V., Rode, Anna K. O., Gravesen, Eva, Olgaard, Klaus, Brunak, Søren, Woetmann, Anders, Ødum, Niels, Bonefeld, Charlotte M., Geisler, Carsten
• Format: Article
• Language: English
• Subjects: HVDRR; Immunology; T cells; vitamin A; vitamin D; vitamin D receptor
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.684015

The active form of vitamin D, 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), 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) 2 D 3 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) 2 D 3 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) 2 D 3 -induced gene regulation was reduced by ~ 50% indicating that the expression level of wild-type VDR determines 1,25(OH) 2 D 3 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) 2 D 3 -induced translocation of the VDR to the nucleus and 1,25(OH) 2 D 3 -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.