To evaluate the in vivo effect of immunosuppressive glucocorticoids on CD4CD25 T regulatory cells, we injected dexamethasone (Dex) into BALB/c mice. Administration of Dex enhanced the proportion of CD4CD25 cells and the ratio of CD4CD25 cells to CD4CD25 cells in the lymphoid organs, especially in the thymus. This correlates with our in vitro observation that CD4CD25 T cells express higher levels of glucocorticoid receptor and Bcl-2, and are therefore more resistant to Dex-mediated cell death than CD4CD25 T cells. Furthermore, IL-2 selectively protected CD4CD25 T cells from Dex-induced cell death, while IL-7 and IL-15 did not exert preferential protective effects. Dex-treated CD4CD25 T cells expressed higher levels of intracellular CTLA-4 and surface glucocorticoid-incluced TNF receptor than fresh CD4CD25 T cells, but still failed to respond to TCR stimulation and inhibited proliferation of CD4CD25 T cells. These results suggest that, in addition to suppressing cytokine transcription, Dex treatment is permissive for the survival of functional CD4CD25 T regulatory cells, and this property may contribute to the anti- inflammatory and immunosuppressive efficacy of glucocorticoids. Our data also suggest that selective protection of CD4CD25 T cell from apoptosis may constitute a role in immune tolerance for IL-2. © 2004 Wiley-VCH Verlag GmbH & Co.