Mitochondrial and lysosomal signaling orchestrates heterogeneous metabolic states of regulatory T cells

Immunotherapies targeting regulatory T (T_reg) cells often trigger inflammation and autoimmunity. How T_reg cells undergo functional reprogramming to reestablish immune homeostasis under these conditions remains unclear. Here, we demonstrate that mitochondrial and lysosomal signaling orchestrates T_reg cell metabolic and functional fitness. T_reg cell–specific loss of the mitochondrial protein Opa1 led to disrupted immune homeostasis and pronounced inflammation, and reduced the generation of T_reg cells with high mitochondrial metabolic and suppressive function. Opa1 deletion triggered mitochondrial bioenergetic stress, associated with increased adenosine monophosphate–activated protein kinase (AMPK) signaling and transcription factor EB (TFEB) activation. Further, T_reg cell–specific deletion of the lysosomal signaling protein Flcn partially phenocopied Opa1 deficiency–associated inflammation and aberrant TFEB activation, and these effects were rectified by TFEB codeletion. Flcn-deficient T_reg cells were enriched in a terminal “metabolic quiescence reset” state and failed to accumulate in nonlymphoid tissues and suppress antitumor immunity. Our study demonstrates that organelle-directed metabolic and signaling processes and mitochondria–lysosome interplay control T_reg cell differentiation and function.