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.