Themis is a T cell lineage-specific molecule that is involved in TCR signal transduction.The effects of germline Themis deletion on peripheral CD4^(+)T cell function have not been described before.In this study,we fou...Themis is a T cell lineage-specific molecule that is involved in TCR signal transduction.The effects of germline Themis deletion on peripheral CD4^(+)T cell function have not been described before.In this study,we found that Themis-deficient CD4^(+)T cells had poor proliferative responses,reduced cytokine production in vitro and weaker inflammatory potential,as measured by their ability to cause colitis in vivo.Resting T cells are quiescent,whereas activated T cells have high metabolic demands.Fulfillment of these metabolic demands depends upon nutrient availability and upregulation of nutrient intake channels after efficient TCR signal transduction,which leads to metabolic reprogramming in T cells.We tested whether defects in effector functions were caused by impaired metabolic shifts in Themis-deficient CD4^(+)T cells due to inefficient TCR signal transduction,in turn caused by the lack of Themis.We found that upon TCR stimulation,Themis-deficient CD4^(+)T cells were unable to upregulate the expression of insulin receptor(IR),glucose transporter(GLUT1),the neutral amino acid transporter CD98 and the mTOR pathway,as measured by c-Myc and pS6 expression.Mitochondrial analysis of activated Themis-deficient CD4^(+)T cells showed more oxidative phosphorylation(OXPHOS)than aerobic glycolysis,indicating defective metabolic reprogramming.Furthermore,we found reduced NFAT translocation in Themis-deficient CD4^(+)T cells upon TCR stimulation.Using previously reported ChIP-seq and RNA-seq data,we found that NFAT nuclear translocation controls IR gene expression.Together,our results describe an internal circuit between TCR signal transduction,NFAT nuclear translocation,and metabolic signaling in CD4^(+)T cells.展开更多
基金This research was supported by the Singapore Ministry of Health’s National Medical Research Council under CBRG/0097/2015the Singapore Ministry of Education under grant 2014-T2-1-136 to N.R.J.G.
文摘Themis is a T cell lineage-specific molecule that is involved in TCR signal transduction.The effects of germline Themis deletion on peripheral CD4^(+)T cell function have not been described before.In this study,we found that Themis-deficient CD4^(+)T cells had poor proliferative responses,reduced cytokine production in vitro and weaker inflammatory potential,as measured by their ability to cause colitis in vivo.Resting T cells are quiescent,whereas activated T cells have high metabolic demands.Fulfillment of these metabolic demands depends upon nutrient availability and upregulation of nutrient intake channels after efficient TCR signal transduction,which leads to metabolic reprogramming in T cells.We tested whether defects in effector functions were caused by impaired metabolic shifts in Themis-deficient CD4^(+)T cells due to inefficient TCR signal transduction,in turn caused by the lack of Themis.We found that upon TCR stimulation,Themis-deficient CD4^(+)T cells were unable to upregulate the expression of insulin receptor(IR),glucose transporter(GLUT1),the neutral amino acid transporter CD98 and the mTOR pathway,as measured by c-Myc and pS6 expression.Mitochondrial analysis of activated Themis-deficient CD4^(+)T cells showed more oxidative phosphorylation(OXPHOS)than aerobic glycolysis,indicating defective metabolic reprogramming.Furthermore,we found reduced NFAT translocation in Themis-deficient CD4^(+)T cells upon TCR stimulation.Using previously reported ChIP-seq and RNA-seq data,we found that NFAT nuclear translocation controls IR gene expression.Together,our results describe an internal circuit between TCR signal transduction,NFAT nuclear translocation,and metabolic signaling in CD4^(+)T cells.
