Mitochondrial complex III is essential for suppressive function of regulatory T cells

Area of Science:

• Immunology
• Cellular Metabolism

Background:

• Regulatory T (Treg) cells are crucial for immune tolerance and homeostasis.
• Treg cells possess a unique metabolic profile with increased mitochondrial metabolism.
• The role of mitochondrial respiration in Treg cell function, stability, and survival was previously unclear.

Purpose of the Study:

• To investigate the necessity of the mitochondrial respiratory chain for Treg cell suppressive capacity, stability, and survival.
• To determine the impact of impaired mitochondrial respiration on Treg cell function and associated molecular mechanisms.

Main Methods:

• Generated mice with T cell-specific ablation of mitochondrial respiratory chain complex III in Treg cells.
• Assessed Treg cell number, proliferation, survival, and suppressive capacity.
• Analyzed gene expression, DNA methylation, and metabolite profiles in Treg cells deficient in complex III.

Main Results:

• Treg cell-specific ablation of complex III led to fatal inflammatory disease in mice.
• Mice lacking complex III in Treg cells showed impaired T cell suppression without affecting Treg cell proliferation or survival.
• Complex III deficiency in Treg cells resulted in decreased expression of Treg function-related genes and stable Foxp3 expression.
• Loss of complex III increased DNA methylation and levels of 2-hydroxyglutarate and succinate, which inhibit TET DNA demethylases.

Conclusions:

• Mitochondrial respiratory chain complex III is essential for Treg cell immune suppressive function.
• Impaired mitochondrial respiration in Treg cells disrupts immune homeostasis and leads to inflammatory disease.
• Complex III activity is required for maintaining Treg cell-specific gene expression and function, potentially through epigenetic regulation.