CD4+ CD25+ regulatory T (T R) cells suppress effector T cells by partly unknown mechanisms. In this study, we describe a population of human suppressive CD4+ CD25+ adaptive T R (T R adapt) cells induced in vitro that express cyclooxygenase 2 (COX-2) and the transcription factor FOXP3. T R adapt cells produce PGE 2 and suppress effector T cell responses in a manner that is reversed by COX inhibitors and PGE 2 receptor-specific antagonists. In resting CD4+ CD25− T cells, treatment with PGE 2 induced FOXP3 expression. Thus, autocrine and paracrine effects of PGE 2 produced by COX-2-positive T R adapt cells may be responsible for both the FOXP3+ phenotype and the mechanism used by these cells to suppress effector T cells.