Obesity reshapes regulatory T cells in the visceral adipose tissue by disrupting cellular cholesterol homeostasis

Regulatory T cells (T_regs) accumulate in the visceral adipose tissue (VAT) to maintain systemic metabolic homeostasis but decline during obesity. Here, we explored the metabolic pathways controlling the homeostasis, composition, and function of VAT T_regs under normal and high-fat diet feeding conditions. We found that cholesterol metabolism was specifically up-regulated in ST2^hi VAT T_reg subsets. T_reg-specific deletion of <i>Srebf2</i>, the master regulator of cholesterol homeostasis, selectively reduced ST2^hi VAT T_regs, increasing VAT inflammation and insulin resistance. Single-cell RNA/T cell receptor (TCR) sequencing revealed a specific loss and reduced clonal expansion of ST2^hi VAT T_reg subsets after <i>Srebf2</i> deletion. <i>Srebf2</i>-mediated cholesterol homeostasis potentiated strong TCR signaling, which preferentially promoted ST2^hi VAT T_reg accumulation. However, long-term high-fat diet feeding disrupted VAT T_reg cholesterol homeostasis and impaired clonal expansion of the ST2^hi subset. Restoring T_reg cholesterol homeostasis rescued VAT T_reg accumulation in obese mice, suggesting that modulation of cholesterol homeostasis could be a promising strategy for T_reg-targeted therapies in obesity-associated metabolic diseases.