Functional reprogramming of regulatory T cells in the absence of Foxp3

Area of Science:

• Immunology
• Cellular Metabolism
• Molecular Biology

Background:

• Regulatory T (Treg) cells are crucial for immune tolerance, controlled by the transcription factor Foxp3.
• Foxp3 deficiency leads to loss of Treg suppressor function and an effector T (Teff) cell phenotype.
• Metabolic dysregulation, including enhanced glycolysis and oxidative phosphorylation, is observed in Foxp3-deficient Tregs.

Purpose of the Study:

• To investigate the role of mammalian target of rapamycin (mTOR) complex 2 (mTORC2) signaling in Foxp3-deficient Tregs.
• To determine if targeting metabolic pathways can restore Treg function in FOXP3 deficiency.
• To explore therapeutic strategies for Treg cell disorders.

Main Methods:

• Utilized genetic deletion of the mTORC2 adaptor gene Rictor in Foxp3-deficient Tregs.
• Assessed the impact of Rictor deletion on Treg cell phenotype, metabolism, and suppressive function.
• Treated Tregs from patients with FOXP3 deficiency using mTOR inhibitors.

Main Results:

• Foxp3 deficiency dysregulates mTORC2 signaling, increasing aerobic glycolysis and oxidative phosphorylation.
• Specific deletion of Rictor in Foxp3-deficient Tregs ameliorated disease via Foxo1.
• Rictor deficiency restored Treg-specific gene circuits and suppressed Teff-like metabolic programs.
• mTOR inhibitors restored suppressive function in Tregs from FOXP3-deficient patients.

Conclusions:

• Targeting metabolic pathways, specifically mTORC2 signaling, can restore regulatory function in Foxp3-deficient Tregs.
• This approach offers a potential therapeutic strategy for immune dysregulation in Treg cell disorders.
• Restoring Treg function by modulating metabolism holds promise for re-establishing immune tolerance.