Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis

Regulatory T (T(reg)) cells respond to immune and inflammatory signals to mediate immunosuppression, but how functional integrity of T(reg) cells is maintained under activating environments remains elusive. Here we found that autophagy was active in T(reg) cells and supported their lineage stability and survival fitness. T(reg) cell-specific deletion of the essential autophagy gene Atg7 or Atg5 led to loss of T(reg) cells, increased tumor resistance, and development of inflammatory disorders. Atg7-deficient T(reg) cells had increased apoptosis and readily lost Foxp3 expression, especially after activation. Mechanistically, autophagy deficiency upregulated mTORC1 and c-Myc function and glycolytic metabolism that contributed to defective T(reg) function. Therefore, autophagy couples environmental signals and metabolic homeostasis to protect lineage and survival integrity of T(reg) cells in activating contexts.