EGFR promotes the apoptosis of CD4+ T lymphocytes through TBK1/Glut1 induced Warburg effect in sepsis

Authors：Huang, Li; Zhang, Xuedi; Fan, Junyu; Liu, Xiaolei; Luo, Shuhua; Cao, Dianqing; Liu, Youtan; Xia, Zhengyuan; Zhong, Hanhui; Chen, Cuiping; Zhang, Liangqing; Liu, Zhifeng^*; Tang, Jing^*

Source：Journal of Advanced Research, 2023, 44: 39-51.

DOI：10.1016/j.jare.2022.04.010

• Sepsis
• EGFR
• CD4+ T lymphocytes
• Activation
• Apoptosis
• Glycolysis

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 sur-vival 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 meta-bolism 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 con-trols 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.

• Institution
  南方医科大学; 广东医学院