Induction of fatal autoimmune myocarditis and other autoimmune diseases in mice by depleting Foxp3-expressing T cells

A transcription factor Foxp3 is predominantly expressed in CD25(+)CD4(+) regulatory T cells (T-R) and controls their development and function. A small fraction of CD25-CD4(+) T cells also express low levels of Foxp3. Here we show that GITR(high) T cells cover all Foxp3(+) T-R cells including both CD25(+) and CD25(-). Complete elimination of Foxp3(+) T-R cells by depleting GITR(high) cells produced more severe form of autoimmune disease in a wider spectrum of organs than depletion of CD25(+) T cells alone. BALB/c mice, for example, developed fatal autoimmune myocarditis and other autoimmune diseases. The results indicate that GITR(high)Foxp3(+) T cells, whether CD25(+) or CD25(-), play key roles in regulating autoimmunity.