Demonstration of circulating allergen-specific CD4+CD25highFoxp3+ T-regulatory cells in both nonatopic and atopic individuals

Background: 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. Objective: To investigate the existence in humans of circulating Treg cells able to recognize exogenous antigens, including allergens. Methods: 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 I allergen or the bacterial antigen streptokinase (SK). Results: 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 I 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. Conclusion: 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 1sensitive, atopic individuals. Clinical implications: Caution should be advised in interpreting allergic disorders as simply resulting from defective Treg cell activity.