Stimulation of Cd25+Cd4+Regulatory T Cells Through Gitr Breaks Immunological Self-Tolerance

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.