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

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.