Background: Regulatory T cells (T regs) are gatekeepers of immune homeostasis and characterized by expression of Foxp3, which maintains T reg identity. The cAMP response element binding protein CREB is suggested to regulate T reg function and expression, however detailed analysis of CREB function in Tregs is lacking. Methods: Mice with a Foxp3-specific knockout of CREB were generated, phenotypically characterized using flow cytometry and serological testing and Tregs were subjected to whole transcriptome, TSDR methylation and ATACseq analysis. An ovalbumin induced asthma model and a T cell transfer colitis model were performed. Results: CREB deficient T regs expand in vivo but show a reduced Foxp3 expression combined with an enhanced expression of ST2, IL-5, IL-13, IL-10, and CREM, while GATA3 was not altered. Enhanced prevalence of ST2 positive Tregs was found in different organs. CREB deficient T regs were suppressive in vitro and prevented disease activity in the Th1 model of T cell mediated transfer colitis in an IL-10 dependent way while Foxp3 CRECREB fl/fl mice showed enhanced ovalbumin mediated asthma severity and spontaneous IgE production. While TSDR methylation was unchanged in CREB deficient T regs, deficiency of CREB alters chromatin accessibility at the ST2, IL13 and CREM locus. Additional genetic CREM deficiency reversed the ST2 phenotype and worsened colitis. Conclusion: Our data suggest that the balance between CREB and CREM expression is important for the regulation of ST2 expression in T regs and for the balance between type 1 and type 2 immune responses.