Copper supports regulatory T cell energetic state to sustain peripheral immune tolerance

Fine-tuning of energy metabolism is essential for the survival and suppressive function of regulatory T cells (T_reg cells). Here, we show that T_reg 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 T_reg cell energetic state. T cell receptor (TCR) stimulation in vitro and human autoimmune conditions increased the labile copper pool in T_reg cells. In murine T_reg cells, we characterized 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 T_reg cell functional molecules. These mechanisms collectively ensured energy production and T_reg 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 T_reg cell functionality and suggest potential therapeutic avenues for autoimmune diseases.