PR002959 (Project)

Description:Fine-tuning of energy metabolism is essential for functionality of regulatory T (Treg) cells. Here, we show that Treg cells with a high energetic state display enhanced functional capacity. Using a screen of mitochondrial inhibitors, we identified copper chelators and ionophores as modulators of Treg cell energetic state. T cell receptor (TCR) stimulation in vitro and human autoimmune conditions increased the labile copper pool in Treg cells. In murine Treg cells, we characterize Slc31a1 as a major copper transporter that supports oxidative phosphorylation, sustains nicotinamide adenine dinucleotide/reduced NAD+ (NAD+/NADH) homeostasis, and promotes histone acetylation at loci encoding core Treg cell functional molecules. These mechanisms collectively ensured energy production and Treg cell functionality, which were indispensable for peripheral immune tolerance but could be rescued by the copper ionophore elesclomol. Together, our findings identify copper metabolism as a critical regulator of Treg cell functionality and suggest potential therapeutic avenues for autoimmune diseases.