Control of CD4+ T cells to restrain inflammatory diseases via eukaryotic elongation factor 2 kinase.

Abstract

CD4+ T cells, particularly IL-17-secreting helper CD4+ T cells, play a central role in the inflammatory processes underlying autoimmune disorders. Eukaryotic Elongation Factor 2 Kinase (eEF2K) is pivotal in CD8+ T cells and has important implications in vascular dysfunction and inflammation-related diseases such as hypertension. However, its specific immunological role in CD4+ T cell activities and related inflammatory diseases remains elusive. Our investigation has uncovered that the deficiency of eEF2K disrupts the survival and proliferation of CD4+ T cells, impairs their ability to secrete cytokines. Notably, this dysregulation leads to heightened production of pro-inflammatory cytokine IL-17, fosters a pro-inflammatory microenvironment in the absence of eEF2K in CD4+ T cells. Furthermore, the absence of eEF2K in CD4+ T cells is linked to increased metabolic activity and mitochondrial bioenergetics. We have shown that eEF2K regulates mitochondrial function and CD4+ T cell activity through the upregulation of the transcription factor, signal transducer and activator of transcription 3 (STAT3). Crucially, the deficiency of eEF2K exacerbates the severity of inflammation-related diseases, including rheumatoid arthritis, multiple sclerosis, and ulcerative colitis. Strikingly, the use of C188-9, a small molecule targeting STAT3, mitigates colitis in a murine immunodeficiency model receiving eEF2K knockout (KO) CD4+ T cells. These findings emphasize the pivotal role of eEF2K in controlling the function and metabolism of CD4+ T cells and its indispensable involvement in inflammation-related diseases. Manipulating eEF2K represents a promising avenue for novel therapeutic approaches in the treatment of inflammation-related disorders.

• Authors: Hao-Yun Peng, Liqing Wang, Jugal Kishore Das, Anil Kumar, Darby J Ballard, Yijie Ren, Xiaofang Xiong, Paul de Figueiredo, Jin-Ming Yang, Jianxun Song
• Journal: Signal transduction and targeted therapy (Signal Transduct Target Ther) Vol. 8 Issue 1 Pg. 415 (10 24 2023) ISSN: 2059-3635 [Electronic] England
• PMID: 37875468 (Publication Type: Journal Article)
• Copyright: © 2023. West China Hospital, Sichuan University.

Chemical References

• Interleukin-17
• Elongation Factor 2 Kinase

Topics

• Mice
• Animals
• Interleukin-17 (genetics)
• Elongation Factor 2 Kinase (genetics, metabolism)
• CD8-Positive T-Lymphocytes (metabolism)
• Inflammation (genetics)
• CD4-Positive T-Lymphocytes