Homeostasis and transitional activation of regulatory T cells require c-Myc

Regulatory T cell (T_reg) activation and expansion occur during neonatal life and inflammation to establish immunosuppression, yet the mechanisms governing these events are incompletely understood. We report that the transcriptional regulator c-Myc (Myc) controls immune homeostasis through regulation of T_reg accumulation and functional activation. Myc activity is enriched in T_regs generated during neonatal life and responding to inflammation. Myc-deficient T_regs show defects in accumulation and ability to transition to an activated state. Consequently, loss of Myc in T_regs results in an early-onset autoimmune disorder accompanied by uncontrolled effector CD4⁺ and CD8⁺ T cell responses. Mechanistically, Myc regulates mitochondrial oxidative metabolism but is dispensable for fatty acid oxidation (FAO). Indeed, T_reg-specific deletion of Cox10, which promotes oxidative phosphorylation, but not Cpt1a, the rate-limiting enzyme for FAO, results in impaired T_reg function and maturation. Thus, Myc coordinates T_reg accumulation, transitional activation, and metabolic programming to orchestrate immune homeostasis.