C-Maf positively regulates IL-17-producing iNKT cell-mediated airway neutrophilia

Abstract

Abstract c-Maf belongs to the large Maf family transcription factors and plays a key role in regulation of cytokine production and differentiation in TH2, TH17, TFH and Tr1 cells. Invariant natural killer T (iNKT) cells can rapidly produce large quantity of TH-related cytokines such as IFN-γ, IL-4 and IL-17A upon stimulation by its glycolipid antigen α-galactosylceramide (α-GalCer). However, the role of c-Maf in iNKT cells and iNKT cell-mediated diseases remains poorly understood. In this study, we demonstrate that α-GalCer-stimulated iNKT cells express c-Maf transcript and protein. By using c-Maf-deficient fetal liver cell-reconstituted mice, we further show that c-Maf-deficient iNKT cells produce less IL-17A than their WT counterparts after α-GalCer stimulation, but IFN-γ and IL-4 productions were not affected. c-Maf deficiency does not affect the development and activation state of iNKT cells. c-Maf also positively regulates induction of IL-17-producing iNKT (iNKT17) cells by IL-6, TGF-β and IL-1β. c-Maf-deficient iNKT cells express lower RORγt transcripts compared with WT iNKT cells under IL-17-induction condition. Interestingly, c-Maf-deficient iNKT17 cells lose the ability to recruit neutrophils into the lungs. Taken together, c-Maf is a positive regulator for IL-17A production through transactivating RORγt expression in iNKT17 cells. It is a potential therapeutic target in iNKT17 cells-mediated inflammatory disease.