Vitamin A-treated natural killer cells reduce interferon-gamma production and support regulatory T cell differentiation

Natural killer (NK) cells are innate cytotoxic lymphocytes that contribute to immune responses against stressed, transformed or infected cells. NK cell effector functions are regulated by microenvironmental factors, including cytokines, metabolites and nutrients. Vitamin A is an essential micronutrient that plays an indispensable role in embryogenesis and development, but was also reported to regulate immune responses. However, the role of vitamin A in regulating NK cell functions remains poorly understood. Here, we show that the most prevalent vitamin A metabolite, all- trans retinoic acid (atRA), induces transcriptional and functional changes in NK cells leading to altered metabolism and reduced IFN-γ production in response to a wide range of stimuli. atRA-exposed NK cells display a reduced ability to support dendritic cell (DC) maturation and to eliminate immature DCs. Moreover, they support the polarization and proliferation of regulatory T cells. These results imply that in vitamin A-enriched environments, NK cells can acquire regulatory-like functions and might promote tolerogenic immunity and/or immunosuppression. ### Competing Interest Statement The authors have declared no competing interest. * A2AR : adenosine A2A receptor atRA : all- trans retinoic acid BM-DCs : bone marrow-derived dendritic cells CD : cluster of differentiation CCL : chemokine (C-C motif) ligand DCs : dendritic cells DMSO : dimethyl sulfoxide ECAR : extracellular acidification rate FCS : fetal calf serum GM-CSF : granulocyte-macrophage colony-stimulating factor ILC3s : group 3 innate lymphoid cells IκBζ : inhibitor of kappa B-zeta IKK α/β : IκB kinase alpha/beta IL : interleukin IFN : interferon mAb : monoclonal antibody MHC : major histocompatibility complex NK : natural killer NIH : National Institutes of Health NFκB : nuclear factor kappa B OCR : oxygen consumption rate PBS : phosphate buffered saline RA : retinoic acid ROS : reactive oxygen species RT : room temperature RPMI : Roswell Park Memorial Institute STAT : signal transducer and activator of transcription Th1 : T helper type 1 Th17 : T helper type 17 TNF : tumor necrosis factor Tregs : regulatory T cells TORC1 : target of Rapamycin Complex 1