Regulatory T (Treg) cells are essential for immune tolerance, but how they maintain functional fitness during inflammation is poorly understood. This study from St. Jude Children's Research Hospital shows that two organelles—mitochondria and lysosomes—work in concert to shape distinct metabolic states within Treg cells. Loss of the mitochondrial fusion protein Opa1 disrupted immune homeostasis and reduced high-functioning Treg cells. Separately, deletion of the lysosomal signaling protein Flcn caused aberrant activation of the transcription factor TFEB, trapping Treg cells in a 'metabolic quiescence reset' state that prevented tissue accumulation and allowed tumor growth. These findings identify organelle-level metabolic signaling as a key controller of Treg cell diversity and suppressive function.
