Interleukin-2 signaling engages de novo cholesterol biosynthesis in regulatory T cells

Abstract

Abstract In the absence of IL-2R signaling, Treg homeostasis is severely disrupted. This is accompanied by a decrease in the expression of enzymes related to cholesterol biosynthesis, but the function of this pathway in Tregs is unknown. To investigate this, we selectively ablated Sterol Regulatory Binding Element Protein 2 by crossing Srebp2flox/flox mice to Foxp3cre mice (Srebp2cKO). Consistent with published studies, homozygous Srebp2cKO mice are outwardly normal. However, when Srebp2cKO Tregs are placed in competition with wild-type Tregs, they are found at a reduced frequency in the spleen, lymph nodes and gut mucosa. In this setting, Srebp2cKO Tregs have reduced Foxp3 expression, suggesting that their function and/or stability may be impacted by altered cholesterol biosynthesis. These defects persist in lymphoid and non-lymphoid tissues when Tregs in competition are treated with an IL-2R agonist. In addition, a marked reduction in effector Treg differentiation is associated with Srebp2cKO Tregs, as expression of CD39, CD73, CD103, Klrg1 and ICOS is reduced while Bcl-2 and CD62L are increased. In response to IL-2R signaling, Srebp2cKO Tregs do not optimally upregulate CD25, which suggests a function for cholesterol biosynthesis in supporting the high affinity IL-2R. These results are consistent with a model whereby IL-2R signaling coordinates Treg cholesterol biosynthesis, which contributes to effector Treg development and raises the possibility that cholesterol biosynthesis could be a target in the therapeutic manipulation of Tregs. Supported by grants from NIH (F30 AI157211-01A1, RO1 AI148675-01)