Slc6a13 deficiency promotes Th17 responses during intestinal bacterial infection

Wenkai Ren,Guoqiang Zhu,Yuexia Liao,Xueyan Ding,Junxia Li,Bie Tan,Yaoyao Xia,Philip R Hardwidge,Guan Yang,Congrui Zhu,Xinming Jia,Ye Jiang,Jielin Duan,Zhijie Lin,Jinping Deng,Jiameng Yan,Yulong Yin

doi:10.1038/s41385-018-0111-7

Abstract

The γ-amino butyric acid (GABA)ergic system shapes the activation and function of immune cells. The present study was conducted to explore the regulation of GABA transporter (GAT)-2 on the differentiation of Th17 cells. Here we found that Th17 cells show higher abundance of GAT-2, and have distinct cellular metabolic signatures, such as the GABA shunt pathway, as compared to naïve T cells. GAT-2 deficiency had little effect on the metabolic signature in naïve T cells, but impaired the GABA uptake and GABA shunt pathway in Th17 cells. GAT-2 deficiency had little effect on T cell development and peripheral T cell homeostasis; however, its deficiency promoted Th17 cell differentiation in vitro. Mechanistically, GAT-2 deficiency promoted differentiation of Th17 cells through activation of GABA–mTOR signaling. In a mouse model of intestinal infection and inflammation, GAT-2 deficiency promoted Th17 responses. Collectively, GAT-2 deficiency promotes Th17 cell responses through activation of GABA–mTOR signaling.

Highlights

The γ-amino butyric acid (GABA)ergic system, which includes GABA, GABA receptors, glutamate decarboxylase (GAD, the enzyme that synthetizes GABA), vesicular inhibitory amino acid transporter (VIAAT; the vesicular protein involved in GABA storage), GABA transporters (GATs) and GABA transaminase (GABA-T, the enzyme that catabolizes GABA), has inhibitory functions in the central nervous system of vertebrates, Increasing investigations are showing that immune cells possess the GABAergic system.[1]
Metabolites with blue color decrease in Th17 cells from Slc6a13–/– mice the role of GAT-2 in regulating peripheral T cell homeostasis, we examined the frequency of T cells in the spleen of the 8 weeks of Slc6a13+/+ and Slc6a13–/– mice
A previous study has shown that GABA promotes intestinal IL-17 expression through mTOR signaling,[6] and GABA signaling has been reported to affect the activation of cellular NF-κB and STAT signaling;[16,17] this study compared the activation of cellular signaling pathways related to Th17 differentiation, including mTOR, p65, and STAT-3.18,19 Slc6a13 deficiency promoted the activation of p65 and mTOR in the Th17 cells, while had little effect on the activation of STAT-3 (Fig. 4a, d–f)

Summary

Introduction

The γ-amino butyric acid (GABA)ergic system, which includes GABA, GABA receptors, glutamate decarboxylase (GAD, the enzyme that synthetizes GABA), vesicular inhibitory amino acid transporter (VIAAT; the vesicular protein involved in GABA storage), GABA transporters (GATs) and GABA transaminase (GABA-T, the enzyme that catabolizes GABA), has inhibitory functions in the central nervous system of vertebrates, Increasing investigations are showing that immune cells possess the GABAergic system.[1]. Slc6a13 deficiency inhibits GABA transport and cellular GABA shunt pathway during Th17 cell differentiation Previous investigation shows that GABA affects Th17 differentiation; we compared the expression of GAT-2 in naïve T cells and Th17 cells.

Results

Conclusion