The transcription factor SREBP2 supports the activation and homeostasis of CD4+ Foxp3+ regulatory T cells

IL-2-STAT5 signaling instructs several metabolic processes underlying Treg activation, including the mevalonate pathway, which is crucial for optimal Treg responses. However, direct links between IL-2-STAT5, mevalonate and Treg function have yet to be established.

To explore this relationship, we deleted sterol regulatory binding element protein 2 (Srebp2), a critical mediator of mevalonate metabolism, selectively in Tregs. Here we show that when Srepb2-deficient Tregs are placed under physiological stress by competing with wild-type Tregs, the former exhibit impaired proliferation, survival, and activation. RNA-seq of Tregs in this competitive setting demonstrate that Srebp2 contributes to pathways controlling IL2R signaling, cholesterol homeostasis, activities associated with the mevalonate pathway, and expression of genes associated with activated Tregs.