Differentiation of IL-17-Producing Invariant Natural Killer T Cells Requires Expression of the Transcription Factor c-Maf

Jhang-Sian Yu; Michito Hamada; Shigeo Ohtsuka; Keigyou Yoh; Satoru Takahashi; Shi-Chuen Miaw

doi:10.3389/fimmu.2017.01399

Differentiation of IL-17-Producing Invariant Natural Killer T Cells Requires Expression of the Transcription Factor c-Maf

Front Immunol. 2017 Oct 27:8:1399. doi: 10.3389/fimmu.2017.01399. eCollection 2017.

Authors

Jhang-Sian Yu¹, Michito Hamada², Shigeo Ohtsuka³, Keigyou Yoh², Satoru Takahashi², Shi-Chuen Miaw¹

Affiliations

¹ Graduate Institute of Immunology, College of Medicine, National Taiwan University, Taipei, Taiwan.
² Faculty of Medicine, Department of Anatomy and Embryology, University of Tsukuba, Ibaraki, Japan.
³ Department of Respiratory Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan.

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 T_H2, T_H17, T_FH, and Tr1 cells. Invariant natural killer T (iNKT) cells can rapidly produce large quantity of T_H-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.

Keywords: IL-17; airway neutrophilia; c-Maf; cytokine regulation; invariant natural killer T cells.