Vitamin D3–VDR and vitamin A‐RAR affect IL‐13 and IFNγ secretion from human CD4+ T cells directly and indirectly via competition for their shared co‐receptor RXR

• Published in: Scandinavian journal of immunology Vol. 101; no. 1; pp. e13429 - n/a
• Main Authors: Stanisic, Tiana, Ewing, Emma Uttrup, Lindell, Alma, Al‐Jaberi, Fatima, Kongsbak‐Wismann, Martin
• Format: Journal Article
• Language: English
• Published: Oxford Wiley Subscription Services, Inc 01.01.2025
• Subjects: Calcitriol; CD4 antigen; CD4+ T cell differentiation; Dietary supplements; Down-regulation; Gene regulation; hereditary vitamin D‐resistant rickets; Immunomodulation; Localization; Lymphocytes; Lymphocytes T; Phenotypes; retinoic acid; retinoic acid receptor; Retinoic acid receptors; retinoid X receptor; Retinoid X receptors; Rickets; Transcription factors; Vitamin A; Vitamin D; vitamin D receptor; Vitamin D receptors; Vitamin D3; γ-Interferon
• ISSN: 0300-9475; 1365-3083; 1365-3083
• DOI: 10.1111/sji.13429

The effects of vitamin D and vitamin A in immune cells are mediated through the vitamin D receptor (VDR) and retinoic acid receptor (RAR), respectively. These receptors share the retinoid X receptor (RXR) co‐factor for transcriptional regulation. We investigated the effects of active vitamin D3 (1,25(OH)2D3) and 9‐cis retinoic acid (9cRA) on T helper (TH)1 and TH2 cytokines and transcription factors in primary human blood‐derived CD4+ 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)2D3 upregulated IL‐13 and suppressed IFNγ, while 9cRA had the opposite effects. This was largely independent of a TH1/TH2 phenotype shift. Combined vitamin supplementation produced intermediate cytokine levels, not only through transcriptional regulation by VDR‐RXR and RAR‐RXR but also through 1,25(OH)2D3 counteracting the effects of 9cRA on solely 9cRA‐responsive genes. Similar results were observed in hereditary vitamin D‐resistant 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‐localization out of the nucleus upon 1,25(OH)2D3 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)2D3 and 9cRA, involving both direct transcriptional regulation and indirect regulation via RXR competitive binding. The vitamin D receptor (VDR) and retinoic acid receptor (RAR) both heterodimerize with the retinoid X receptor (RXR) for gene regulation. Beyond directly regulating genes through DNA interactions, we find that the receptors also indirectly regulate transcription by competing for RXR, and by upregulating genes modulating their own direct functions.