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

Periodic activation of regulatory T cells (Tregs) is necessary to restrict autoreactive T cells and maintain immune homeostasis. 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 Srebp2-deficient Tregs are placed under physiological stress by competing with wild-type Tregs, the former exhibit impaired proliferation, survival, and activation. RNA sequencing of Tregs in this competitive setting demonstrate that Srebp2 contributes to pathways controlling IL-2R signaling, cholesterol homeostasis, activities associated with the mevalonate pathway, and expression of genes associated with activated Tregs. These findings link Srebp2, the IL-2R, and the mevalonate pathways for efficient Treg homeostasis and activation. These effects, however, require a competitive setting, as mice with only Srebp2-deficient Tregs were outwardly normal with respect to their development, homeostasis, metabolic activity, and function. Thus, Srebp2 is necessary to optimally tune Treg homeostasis and activation, but sufficient redundancy exists to compensate for the lack of Srebp2 to maintain Treg development and function in the absence of physiological stress.