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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.