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

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. (c) 2022 The Authors. Published by Elsevier B.V. on behalf of Cairo University. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Automated summary

This study found that EGFR can affect the activation and apoptosis of CD4+ T cells by promoting Glut1 transportation, leading to immune dysfunction in sepsis. The levels of EGFR and Glut1 expression and the activation levels of CD4+ T cells were significantly higher in sepsis patients compared to healthy individuals.