Vitamin D-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.

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 D (1,25(OH)D) and 9-cis retinoic acid (9cRA) on T helper (T)1 and T2 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)D upregulated IL-13 and suppressed IFNγ, while 9cRA had the opposite effects. This was largely independent of a T1/T2 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)D 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)D 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)D and 9cRA, involving both direct transcriptional regulation and indirect regulation via RXR competitive binding.