CD25+CD4+ regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance. We show here that glucocorticoid-induced tumor necrosis factor receptor family−related gene (GITR, also known as TNFRSF18)—a member of the tumor necrosis factor−nerve growth factor (TNF-NGF) receptor gene superfamily—is predominantly expressed on CD25+CD4+ T cells and on CD25+CD4+CD8- thymocytes in normal naïve mice. We found that stimulation of GITR abrogated CD25+CD4+ T cell−mediated suppression. In addition, removal of GITR-expressing T cells or administration of a monoclonal antibody to GITR produced organ-specific autoimmune disease in otherwise normal mice. Thus, GITR plays a key role in dominant immunological self-tolerance maintained by CD25+CD4+ regulatory T cells and could be a suitable molecular target for preventing or treating autoimmune disease.
