RESUMEN
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 functions that might promote tolerogenic immunity and/or immunosuppression.
Asunto(s)
Diferenciación Celular , Células Dendríticas , Interferón gamma , Células Asesinas Naturales , Linfocitos T Reguladores , Vitamina A , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/efectos de los fármacos , Interferón gamma/metabolismo , Diferenciación Celular/inmunología , Diferenciación Celular/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Humanos , Vitamina A/metabolismo , Vitamina A/farmacología , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Tretinoina/farmacología , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Células Cultivadas , Tolerancia Inmunológica/efectos de los fármacosRESUMEN
eIF2B is the guanine nucleotide exchange factor (GEF) required for cytoplasmic protein synthesis initiation in eukaryotes and its regulation within the integrated stress response (ISR). It activates its partner factor eIF2, thereby promoting translation initiation. Here we provide evidence through biochemical and genetic approaches that eIF2B can bind directly to GTP and this can enhance its rate of GEF activity toward eIF2-GDP in vitro. GTP binds to a subcomplex of the eIF2Bγ and ε subunits. The eIF2Bγ amino-terminal domain shares structural homology with hexose sugar phosphate pyrophosphorylase enzymes that bind specific nucleotides. A K66R mutation in eIF2Bγ is especially sensitive to guanine or GTP in a range of functional assays. Taken together, our data suggest eIF2Bγ may act as a sensor of purine nucleotide availability and thus modulate eIF2B activity and protein synthesis in response to fluctuations in cellular nucleotide levels.