IL-2 is crucial for the production of CD4+CD25+T regulatory (Treg) cells whileimportant for the generation of effective T cell-mediated immunity. How to exploit thecapacity of IL-2 to expand Treg cells, while restraining activation of T effector (Teff)cells, is an important and unanswered therapeutic question. Dexamethasone (Dex), asynthetic glucocorticoid steroid, has been reported to suppress IL-2-mediated activationof Teff cells and increase the proportion of Treg cells. Thus, we hypothesized thatglucocorticoids may be useful as costimulants to amplify IL-2-mediated selectiveexpansion of Treg cells. We show in this study that short-term simultaneousadministration of Dex and IL-2 markedly expanded functional suppressiveFoxp3+CD4+CD25+T cells in murine peripheral lymphoid tissues. In a myelinoligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis(EAE) mouse model, we observed that splenic CD4+CD25+Tcells failed to suppress theproliferation of CD4+CD25–T cells. Pretreatment with Dex/IL-2 remarkably increasedthe proportion of CD4+FoxP3+cells and partially restored the function of splenicCD4+CD25+Tcells, and inhibited the development of EAE. Therefore, the combinationof glucocorticoid and IL-2, two currently used therapeutics, may provide a novelapproach for the treatment of autoimmune diseases, transplant rejection and graft-vs.-host disease.