Vitamin D Receptor, STAT3 and TET2 Cooperate to Establish Tolerogenesis

The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), induces stable tolerogenic phenotype in dendritic cells (DCs). This process involves the vitamin D receptor (VDR), which translocates to the nucleus, binds its cognate genomic sites and promotes epigenetic and transcriptional remodeling. In this study, we report the occurrence of vitamin D-specific DNA demethylation and transcriptional activation at VDR binding sites associated with the acquisition of tolerogenesis. Tolerogenic properties of DCs are acquired together with activation of the IL6-JAK-STAT3 pathway. In fact, ChIP-seq analysis shows that VDR directly binds the IL6 gene, and JAK2-mediated STAT3 phosphorylation is specific to vitamin D stimulation. VDR and the phosphorylated form of STAT3 interact with each other to form a complex with methylcytosine dioxygenase TET2. Most importantly, pharmacological inhibition of STAT3 phosphorylation reverts vitamin D-induced tolerogenic properties of DCs. This novel interplay between VDR, STAT3 and TET2 opens up possibilities for modulating DC immunogenic properties in the clinics.