Using Foxp3CRECREBfl/fl mice, we herein confirm the colitis phenotype but can show that i) CREB deficiency in Tregs induces expression of ST2+Tregs, ii) the phenotype that prevents colitis in Rag2-/- mice is primarily dependent on abundance of IL-10, and iii) this phenotype can be reversed by knockout of CREM, which lowers the expression of ST2. Here, CREM is linked to colitis.