Increased production of IFN-γ by natural killer cells triggered with bone marrow-derived dendritic cells cultured in the presence of retinoic acid

Abstract

All-trans-retinoic acid (RA), a vitamin A metabolite, is beginning to be explored as an immunopharmacologic agent. While its effects on dendritic cells and the induction of regulatory T cells have been recognized, little is known about the effect of RA on dendritic cell–natural killer cell (DC–NK) crosstalk. DC–NK crosstalk is important in directing the innate immune response, as well as subsequent adaptive immune response during viral infection, cancer, pregnancy, as well as organ transplantation. Here we demonstrate with flow cytometry and cytokine bead array analysis, that bone marrow derived dendritic cells (BMDCs) cultured in the presence of ≥98% HPLC purified RA (RA-DCs) were suppressed in their ability to mature in response to TLR stimulation. 1µM of RA was found to be optimal without affecting the percentage of DCs in culture. Upregulation of MHCII and costimulatory molecule CD86, as well as IL-12 secretion were inhibited by RA treatment. RA-DCs differentially modulate NK cell function compared to BMDCs. In vitro co-culture of RA-DCs with NK cells reveal increased IFN-γ secretion. Increased production of IFN-γ in lung NK cells was also demonstrated when RA-DCs were injected into the tail vein. Our results suggest that RA-DCs exhibit a regulatory phenotype and function, which differentially modulates NK cell function. Furthermore, IFN-γ has various regulatory and immunological functions, depending on the immunological context. The effect of RA-DCs needs to be further explored in the context of a disease in order to understand the regulatory effects of retinoic acid.