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.

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 (T_H)1 and T_H2 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 T_H1/T_H2 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.