The AP-1 transcription factor JunB is required for Th17 cell differentiation

Soh Yamazaki,Ryodai Shindo,Shogo Endo,Takaharu Katagiri,Xuefeng Duan,Akira Kohda,Tomoko Arasaki,Fumihito Miura,Fumiyuki Sanematsu,Takashi Ito,Hiromitsu Araki,Hiroyasu Nakano,Yoshihiko Tanaka,Yoshinori Fukui,Hideki Sumimoto

doi:10.1038/s41598-017-17597-3

Abstract

Interleukin (IL)-17-producing T helper (Th17) cells are crucial for host defense against extracellular microbes and pathogenesis of autoimmune diseases. Here we show that the AP-1 transcription factor JunB is required for Th17 cell development. Junb-deficient CD4+ T cells are able to develop in vitro into various helper T subsets except Th17. The RNA-seq transcriptome analysis reveals that JunB is crucial for the Th17-specific gene expression program. Junb-deficient mice are completely resistant to experimental autoimmune encephalomyelitis, a Th17-mediated inflammatory disease, and naive T helper cells from such mice fail to differentiate into Th17 cells. JunB appears to activate Th17 signature genes by forming a heterodimer with BATF, another AP-1 factor essential for Th17 differentiation. The mechanism whereby JunB controls Th17 cell development likely involves activation of the genes for the Th17 lineage-specifying orphan receptors RORγt and RORα and reduced expression of Foxp3, a transcription factor known to antagonize RORγt function.

Highlights

Interleukin (IL)-17–producing CD4+ T helper (Th17) cells are a key immune cell lineage that protects against extracellular microbe infection[1,2] and is critically associated with inflammatory autoimmune diseases, e.g., experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis[3,4]
When OT-II mice-derived CD4+ T cells[22] were cultured with the chicken ovalbumin peptide OVA323–339 and splenic antigen-presenting cells (APCs) under Th17-polarizing conditions, Junb-deficient OT-II T cells differentiated into IL-17A-producing cells much less efficiently than control cells (Fig. 1D)
The present study provides genetic evidence that JunB is required for Th17 cell differentiation: Junb-deficient CD4+ T cells are defective in differentiating into Th17 cells, and Junb-deficient mice are refractory to induction of the Th17 cell-dependent autoimmunity EAE

Summary

Introduction

Interleukin (IL)-17–producing CD4+ T helper (Th17) cells are a key immune cell lineage that protects against extracellular microbe infection[1,2] and is critically associated with inflammatory autoimmune diseases, e.g., experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis[3,4]. RORγt expression is elevated by the transcription factor STAT3, which functions downstream of the receptor for the Th17-polarizing cytokine IL-6 and plays a crucial role in Th17 cell differentiation[9]. BATF is known to function in Th17 cells and in a variety of immune cells, which is probably mediated by leucine-zipper-mediated formation of the activator protein-1 (AP-1) complex with a transcription factor of the Jun family[15,16,17,18]. This family contains three members, i.e., c-Jun, JunB, and JunD. JunB appears to control Th17 cell specification by inducing activation of Rorc and Rora and by reducing expression of Foxp[3]

Methods

Results

Conclusion