Functional reprogramming of regulatory T cells in the absence of Foxp3

LM Charbonnier, Y Cui, E Stephen-Victor, H Harb… - Nature …, 2019 - nature.com
LM Charbonnier, Y Cui, E Stephen-Victor, H Harb, D Lopez, JJ Bleesing, MI Garcia-Lloret…
Nature immunology, 2019nature.com
Regulatory T cells (Treg cells) deficient in the transcription factor Foxp3 lack suppressor
function and manifest an effector T (Teff) cell–like phenotype. We demonstrate that Foxp3
deficiency dysregulates metabolic checkpoint kinase mammalian target of rapamycin
(mTOR) complex 2 (mTORC2) signaling and gives rise to augmented aerobic glycolysis and
oxidative phosphorylation. Specific deletion of the mTORC2 adaptor gene Rictor in Foxp3-
deficient Treg cells ameliorated disease in a Foxo1 transcription factor–dependent manner …
Abstract
Regulatory T cells (Treg cells) deficient in the transcription factor Foxp3 lack suppressor function and manifest an effector T (Teff) cell–like phenotype. We demonstrate that Foxp3 deficiency dysregulates metabolic checkpoint kinase mammalian target of rapamycin (mTOR) complex 2 (mTORC2) signaling and gives rise to augmented aerobic glycolysis and oxidative phosphorylation. Specific deletion of the mTORC2 adaptor gene Rictor in Foxp3-deficient Treg cells ameliorated disease in a Foxo1 transcription factor–dependent manner. Rictor deficiency re-established 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 re-established in Foxp3-deficient Treg cells by targeting their metabolic pathways, providing opportunities to restore tolerance in Treg cell disorders.
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