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EGFR promotes the apoptosis of CD4+ T lymphocytes through TBK1/Glut1 induced Warburg effect in sepsis
Journal of Advanced Research  (IF12.822),  Pub Date : 2022-05-01, DOI: 10.1016/j.jare.2022.04.010
Li Huang, Xuedi Zhang, Junyu Fan, Xiaolei Liu, Shuhua Luo, Dianqing Cao, Youtan Liu, Zhengyuan Xia, Hanhui Zhong, Cuiping Chen, Liangqing Zhang, Zhifeng Liu, Jing Tang

Introduction

Sepsis-induced apoptosis leads to lymphopenia including the decrease of CD4+ T cells thus favoring immunosuppression.

Objectives

Although epidermal growth factor receptor (EGFR) inhibitors significantly improve the survival rate of septic mice, the effect of EGFR on the function and metabolism of CD4+ T cells in sepsis remained unknown.

Methods

CD4+ T cells from septic mice and patients were assessed for apoptosis, activation, Warburg metabolism and glucose transporter 1 (Glut1) expression with or without the interference of EGFR activation.

Results

EGFR facilitates CD4+ T cell activation and apoptosis through Glut1, which is a key enzyme that controls glycolysis in T cells. EGFR, TANK binding kinase 1 (TBK1) and Glut1 form a complex to facilitate Glut1 transportation from cytoplasm to cell surface. Both the levels of membrane expression of EGFR and Glut1 and the activation levels of CD4+ T cells were significantly higher in patients with sepsis as compared with healthy subjects.

Conclusion

Our data demonstrated that through its downstream TBK1/Exo84/RalA protein system, EGFR regulates Glut1 transporting to the cell surface, which is a key step for inducing the Warburg effect and the subsequent cellular activation and apoptosis of CD4+ T lymphocytes and may eventually affect the immune functional status, causing immune cell exhaustion in sepsis.