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.