Abstract
c-Maf belongs to the large Maf family of transcription factors and plays a key role in the regulation of cytokine production and differentiation of 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 glycolipid antigens, such as α-galactosylceramide (α-GalCer). However, the role of c-Maf in iNKT cells and iNKT cells-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 wild-type counterparts after α-GalCer stimulation. While c-Maf deficiency does not affect the development and activation of iNKT cells, c-Maf is essential for the induction of IL-17-producing iNKT (iNKT17) cells by IL-6, TGF-β, and IL-1β, and the optimal expression of RORγt. Accordingly, c-Maf-deficient iNKT17 cells lose the ability to recruit neutrophils into the lungs. Taken together, c-Maf is a positive regulator for the expression of IL-17A and RORγt in iNKT17 cells. It is a potential therapeutic target in iNKT17 cell-mediated inflammatory disease.
Highlights
Natural killer T (NKT) cells are a subset of lymphocytes that bridge innate and adaptive immunity [1]
The most well-studied NKT cells are the CD1d-dependent invariant NKT cells which have a limited repertoire of αβTCR chains, allowing them to recognize glycolipid antigens [e.g., α-galactosylceramide (α-GalCer)] presented by CD1d molecules expressed by antigen-presenting cells (APCs) [7]
Since only invariant NKT (iNKT) cells respond to α-GalCer, our results indicate that c-Maf is a positive regulator for IL-17A production in α-GalCer-activated iNKT cells
Summary
Natural killer T (NKT) cells are a subset of lymphocytes that bridge innate and adaptive immunity [1]. Recent studies have demonstrated that c-Maf is expressed in other immune cells, including TH17, TFH, and LPS-activated macrophages, and regulates the expression of IL-22, IL-21, and IL-10 [14,15,16,17]. C-Maf interacted with Sox and cooperatively induced TH17 cell differentiation via induction of RORγt [19]. These finding strongly suggest that c-Maf plays a direct role in IL-17A production in TH17 cells. We used a genetic approach to demonstrate that c-Maf is expressed in α-GalCer-activated iNKT cells. We further show that c-Maf is required for the optimal expression of RORγt and IL-17, but not IFN-γ or IL-4, in iNKT cells and is essential for their ability to induce airway neutrophilic inflammation in vivo
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