Preview

PDF, English Download (7MB) | Terms of use

Abstract

Vitamin A, a fat-soluble micronutrient, plays an indispensable role in embryogenesis and de-velopment, and was also reported to regulate immune responses. In mammals, Vitamin A-enriched tissues, such as liver, gut or fat, comprise various immune cells. NK cells as circulat-ing innate lymphocytes are frequently recruited to tissues during inflammatory responses. NK cells contribute to tissue homeostasis by eliminating abnormal cells and modulating immune responses. However, the influence of vitamin A in regulating NK cell-mediated immune re-sponses remains unclear. Here, we investigated the effect of the vitamin A metabolite, all-trans retinoic acid (atRA) on murine NK cells. We showed that atRA induced transcriptional and phenotypic reprogram-ming of NK cells, depicted as altered expression of transcription factors, receptors, adhesion molecules and metabolizing-enzymes. In addition, atRA altered effector functions of NK cells, which led to a reduced production of inflammatory cytokines, such as interferon gamma (IFN-γ), in response to various stimuli. Our data revealed that atRA reduced ability of NK cells to induce maturation of dendritic cells (DCs) or to remove DCs, resulting in an increased number of immature antigen presenting cells. NK cells treated with atRA supported FoxP3 expression and proliferation of these cells, providing “Treg-friendly” microenvironment. Furthermore, atRA altered mitochondrial fitness and metabolisms of NK cells by enhancing mitochondrial respiration. Peroxisome proliferator-activated receptor gamma (PPARγ), a nu-clear receptor, was abundantly expressed by NK cells upon exposure to atRA. The condition-al deletion of PPARγ in NK cells caused impaired glycolysis and mitochondrial respiration, and the malfunction of metabolism of NK cells was rescued by atRA. In summary, we identify a novel role of vitamin A in shaping molecular and functional charac-teristics of NK cells. We demonstrate regulatory functions of NK cells in the vitamin A-enriched microenvironment to regulate other immune cells, which might contribute to tolero-genic immune responses.