ABSTRACT Dendritic cells (DCs) are central in the immune system, bridging the adaptive and innate immune responses. Research on in vitro differentiation of DCs from monocytes provides both in-depth understanding of the analogous in vivo process and potential sources for cancer cell therapy. Active DNA demethylation is crucial in DC differentiation. Vitamin C is a known cofactor of ten-eleven translocation (TET) enzymes, which drive active demethylation. Currently, the effects of vitamin C treatment on human immune cells are poorly understood. In this study, we have studied the epigenomic and transcriptomic reprogramming orchestrated by vitamin C in monocyte-derived DC differentiation and maturation. Vitamin C triggers extensive demethylation at NF-kB/p65 binding sites, together with concordant upregulation of antigen-presentation immune response-related genes during DC maturation. p65 interacts with TET2 and mediates the aforementioned vitamin C-mediated changes, as demonstrated by pharmacological inhibition. Moreover, vitamin C increases TNFβ production in DCs through NF-kB, in concordance with the upregulation of its coding gene and the demethylation of adjacent CpGs. Finally, vitamin C enhances DC’s ability to stimulate the proliferation of autologous antigen-specific T cells. We propose that vitamin C can improve monocyte-derived DC-based cell therapies. Finally, our results provide a feasible mechanism of action for intravenous high-dose vitamin C treatment in patients.

Vitamin C triggers NF-κB-driven epigenomic reprogramming and enhanced immunogenic responses of dendritic cells