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Themis regulates metabolic signaling and effector functions in CD4^(+) T cells by controlling NFAT nuclear translocation

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Cellular & Molecular Immunology 2021年第9期18卷 2249-2261页

作者： Mukul Prasad Joanna Brzostek Namrata Gautam Renu Balyan vasily rybakin Nicholas R.J.Gascoigne Translational Immunology Programme Yong Loo Lin School of MedicineNational University of Singapore5 Science Drive 2Singapore 117545Singapore Department of Microbiology and Immunology Yong Loo Lin School of MedicineNational University of Singapore5 Science Drive 2Singapore 117545Singapore H.Lee Moffitt Cancer Center and Research Institute TampaFLUSA Torque Therapeutics CambridgeMAUSA

Themis is a T cell lineage-specific molecule that is involved in TCR signal *** effects of germline Themis deletion on peripheral CD4^(+)T cell function have not been described *** 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 *** T cells are quiescent,whereas activated T cells have high metabolic *** 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 *** 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 *** 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 *** analysis of activated Themis-deficient CD4^(+)T cells showed more oxidative phosphorylation(OXPHOS)than aerobic glycolysis,indicating defective metabolic ***,we found reduced NFAT translocation in Themis-deficient CD4^(+)T cells upon TCR *** previously reported ChIP-seq and RNA-seq data,we found that NFAT nuclear translocation controls IR gene ***,our results describe an internal circuit between TCR signal transduction,NFAT nuclear translocation,and metabolic signaling in CD4^(+)T cells.

关键词： Immunometabolism NFAT nuclear translocation Insulin receptor mTOR Mitochondria

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