Akademik Veri Yönetim Sistemi
Özen A. O., Chatila T. A.(Yürütücü)
Diğer Uluslararası Fon Programları, 2013 - 2018
Regulatory T cells (Treg cells) deficient in the transcription factor Foxp3 lack suppressor function and manifest a T effector (Teff) cell-like phenotype. We demonstrate that Foxp3 deficiency dysregulates metabolic checkpoint kinase mTORC2 signaling and gives rise to augmented aerobic glycolysis and oxidative phosphorylation. Specific deletion of the mTORC2 adaptor gene Rictor in Foxp3-deficient Tregcells ameliorated disease in a Foxo1 transcription factor-dependent manner. Rictor deficiency reestablished a subset of Treg cell genetic circuits and suppressed the Teff cell-like glycolytic and respiratory programs, which contributed to immune dysregulation. Treatment of Treg cells from patients with FOXP3 deficiency with mTOR inhibitors similarly antagonized their Teff cell-like program and restored suppressive function. Thus, regulatory function can be reestablished in Foxp3-deficient Treg cells by targeting their metabolic pathways, providing opportunities to restore tolerance in Treg cell disorders.