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

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

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish
Article number415
JournalSignal Transduction and Targeted Therapy
Volume8
Issue number1
DOIs
StatePublished - Dec 2023

Bibliographical note

Publisher Copyright:
© 2023, West China Hospital, Sichuan University.

ASJC Scopus subject areas

  • Genetics
  • Cancer Research

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