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.
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