CD4 + CD25 + Foxp3 + T-regulatory (Treg) cells play a fundamental role in the control of autoimmunity. Whether human CD4 + CD25 + Foxp3 + Treg cells that recognize foreign antigens also exist is less clear.To investigate the existence in humans of circulating Treg cells able to recognize exogenous antigens, including allergens.CD4 + CD25 high Foxp3 + and CD4 + CD25 - Foxp3 - cells were purified from human peripheral blood and cultured for 15 days with autologous dendritic cells (DCs), unloaded, or loaded with Der p 1 allergen or the bacterial antigen streptokinase (SK).CD4 + CD25 high Foxp3 + circulating T cells obtained from healthy nonatopic subjects and cultured with Der p 1–loaded DCs, but not those cultured with either unloaded or SK-loaded DCs, suppressed the proliferative response to Der p 1 of autologous Der p 1–specific T cells generated from the CD4 + CD25 - Foxp3 - subset. The antigen specificity of either Der p 1–CD4 + CD25 high Foxp3 + or SK–CD4 + CD25 high Foxp3 + T cells was confirmed even at clonal level. Finally, under the same experimental conditions, functionally active Der p 1–specific Treg cells were obtained from the pool of circulating CD4 + CD25 high Foxp3 + T cells of Der p 1–sensitive, atopic individuals.These data provide undoubted demonstration of the existence of human CD4 + CD25 high Foxp3 + circulating Treg cells specific for exogenous antigens, including the Der p 1 allergen, and indicate that CD4 + CD25 high Foxp3 + Treg cells specific for Der p 1 are present and functionally active in both nonatopic and Der p 1–sensitive, atopic individuals.Caution should be advised in interpreting allergic disorders as simply resulting from defective Treg cell activity.