DGK α and ζ Activities Control TH1 and TH17 Cell Differentiation.

Jialong Yang,Jinli Wang,Edwin C K Wan,Hong-Xia Wang,Xiao-Ping Zhong,Lei Li,Jinhai Xie

doi:10.3389/fimmu.2019.03048

Abstract

CD4+ T helper (TH) cells are critical for protective adaptive immunity against pathogens, and they also contribute to the pathogenesis of autoimmune diseases. How TH differentiation is regulated by the TCR's downstream signaling is still poorly understood. We describe here that diacylglycerol kinases (DGKs), which are enzymes that convert diacylglycerol (DAG) to phosphatidic acid, exert differential effects on TH cell differentiation in a DGK dosage-dependent manner. A deficiency of either DGKα or ζ selectively impaired TH1 differentiation without obviously affecting TH2 and TH17 differentiation. However, simultaneous ablation of both DGKα and ζ promoted TH1 and TH17 differentiation in vitro and in vivo, leading to exacerbated airway inflammation. Furthermore, we demonstrate that dysregulation of TH17 differentiation of DGKα and ζ double-deficient CD4+ T cells was, at least in part, caused by increased mTOR complex 1/S6K1 signaling.

Highlights

CD4+ T helper (TH) cells play a central role in orchestrating adaptive immune response to pathogens and contribute to autoimmune diseases [1, 2]
We found that DGKα mRNA was decreased in TH0, TH1, TH2, TH17, and iTregs compared with naïve CD4+ T cells
DGKζ mRNA was decreased in TH0, TH1, and TH17 cells but not in TH2 and iTregs compared with naïve CD4+ T cells (Figure 1A)

Summary

Introduction

CD4+ T helper (TH) cells play a central role in orchestrating adaptive immune response to pathogens and contribute to autoimmune diseases [1, 2]. Interferon-γ (IFN-γ)-producing TH1 cells, induced by IL-12 and directed by transcriptional factor T-bet, are critical for the clearance of intracellular pathogens [3, 4]. TH2 cells, which secrete IL-4, IL-5, and IL-13 and are controlled by GATA-3, are crucial for protection against parasites and extracellular pathogens [5, 6]. TH17 cells produce IL-17A, IL-17F, and IL-22, and play an important role in the control of specific pathogens such as fungi. TH17 differentiation is driven by a combination of TGF-β and IL-6 and requires transcriptional factor RORγt and RORα. IL-23 promotes TH17 responses by enhancing their survival and stabilization [7,8,9,10,11,12]

Methods

Results

Conclusion