CREB determines the expression of ST2 in Tregs and mediates the balance between type 1 and type 2 immune responses

Regulatory T cells (Tregs) are gatekeepers of immune homeostasis and characterized by expression of Foxp3, which maintains Treg identity. The cAMP response element binding protein CREB binds the TSDR and influences Foxp3 expression. To understand the functional consequences, we generated mice with a Foxp3-specific knockout of CREB. CREB deficient Tregs expand in vivo but show a reduced Foxp3 expression combined with an enhanced expression of IL-5, IL-13, IL-10, ST2 and CREM. This renders such Tregs highly suppressive in vitro and prevents disease activity in the Th1 model of T cell mediated transfer colitis in an IL-10 dependent way while it enhanced ovalbumin mediated asthma severity. While TSDR methylation was unchanged in CREB deficient Tregs, CREB and CREM directly interact with Foxp3 and deficiency of CREB alters chromatin accessibility at the IL13 and ST2 locus. Additional genetic CREM deficiency reverses the ST2 phenotype. Our data suggest that CREB expression in Tregs is important for the regulation of ST2 mediated balance between type 1 and type 2 immune responses.