CD4(+)CD25(+) regulatory T cells (CD4(+)CD25(+) Tregs) play a critical role in the maintenance of peripheral self-tolerance and the regulation of immune responses. Genetic defects that primarily affect the development and/or function of CD4(+)CD25(+) Tregs result in severe autoimmune diseases and inflammatory disorders. In this study, we investigated whether the peripheral pool and the function of CD4(+)CD25(+) Tregs are altered in patients of myasthenia gravis (MG), a chronic autoimmune disorder that results in progressive skeletal muscle weakness. Here we showed that both mRNA and protein expression level of FoxP3 in CD4(+)CD25(+) Tregs are dramatically down-regulated, accompanied by an severe functional defect in CD4(+)CD25(+) Tregs regulatory activity when cocultured with autologous CD4(+)CD25(-) Tcells, although the reservoir of CD4(+)CD25(+) Tregs is not changed in peripheral blood from MG patients. Since FoxP3 is a pivotal transcription factor that indispensable for the generation and the regulatory function of CD4(+)CD25(+) Tregs, our data suggested that the functional activity of CD4(+)CD25(+) Tregs is inhibited in MG patients and that MG might originate from the dysfunction of CD4(+)CD25(+) Tregs. Although the underlying molecular basis for the reduced expression of FoxP3 in CD4(+)CD25(+) Tregs from MG patients remains unknown, this study provided a potential target for MG therapy. (C) 2008 Elsevier B.V. All rights reserved.