Copper control of the suppressive capacity in regulatory T cells [CUT&Tag]

Fine-tuning nutrient flow and energy production is required to sustain the functionality and survival of Tregs, yet key factors and pathways remain to be identified. Here, we show that, mitochondrial activity is a superior property over activation markers for Treg functionality. Through a screen of mitochondrial inhibitory compounds, we reveal that copper chelators/ionophores modulate mitochondrial activity. Tregs activated in vitro and from individuals with psoriasis and rheumatoid arthritis obscure a greater labile copper pool compared to controls. We characterize Slc31a1 as a major copper transporter in Treg, which supports oxidative phosphorylation, energy production and histone acetylation at the gene loci of suppressive genes to maintain the transcription of suppressive molecules and Treg functionality. This process is vital for peripheral immune tolerance. Our findings underscore the role of copper metabolism in Treg biology, which may offer therapeutic strategy for treating autoimmune diseases.