Regulation of murine inflammatory bowel disease by CD25⁺ and CD25^- CD4⁺ glucocorticoid-induced TNF receptor family-related gene⁺ regulatory T cells

CD4⁺CD25⁺ regulatory T cells in normal animals are engaged in the maintenance of immunological self-tolerance and prevention of autoimmune disease. However, accumulating evidence suggests that a fraction of the peripheral CD4⁺CD25^- T cell population also possesses regulatory activity in vivo. Recently, it has been shown glucocorticoid-induced TNFR family-related gene (GITR) is predominantly expressed on CD4⁺CD25⁺ regulatory T cells. In this study, we show evidence that CD4+GITR+ T cells, regardless of the CD25 expression, regulate the mucosal immune responses and intestinal inflammation. SCID mice restored with the CD4⁺GITR^- T cell population developed wasting disease and severe chronic colitis. Cotransfer of CD4⁺GITR⁺ population prevented the development of CD4⁺CD45RB^high T cell-transferred colitis. Administration of anti-GITR mAb-induced chronic colitis in mice restored both CD45RB^high and CD45RB^low CD4⁺ T cells. Interestingly, both CD4⁺CD25⁺ and CD4⁺CD25^- GITR⁺ T cells prevented wasting disease and colitis. Furthermore, in vitro studies revealed that CD4⁺CD25^-GITR⁺ T cells as well as CD4⁺CD25⁺GITR⁺ T cells expressed CTLA-4 intracellularly, showed anergic, suppressed T cell proliferation, and produced IL-10 and TGF-β. These data suggest that GITR can be used as a specific marker for regulatory T cells controlling mucosal inflammation and also as a target for treatment of inflammatory bowel disease.