Functional reprogramming of regulatory T cells in the absence of Foxp3

Nature Immunology
Louis-Marie CharbonnierTalal A Chatila

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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Methods Mentioned

BETA
immunoprecipitation
ubiquitination
PCR
reverse transcription PCR
flow cytometry
FCS
electrophoresis
Assay
pull down
ChIP

Software Mentioned

Image J
DIVA
R64
FastQC
ImageJ
ZEN
STAR62
DESeq2
FlowJo

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