Peripheral T cells become sensitive to glucocorticoid- and stress-induced apoptosis in transgenic mice overexpressing SRG3

Immature double-positive thymocytes are sensitive to glucocorticoid (GC)-in duced apoptosis, whereas mature single-positive T cells are relatively resi stant. Thymocytes seem to acquire resistance to GCs during differentiation into mature single-positive thymocytes. However, detailed knowledge concern ing what determines the sensitivity of thymocytes to GCs and how GC sensiti vity is regulated in thymocytes during development is lacking. We have prev iously reported that the murine SRG3 gene (for SW13-related gene) is requir ed for GC-induced apoptosis in a thymoma cell line. Herein, we provide resu lts suggesting that the expression level of SRG3 protein determines the GC sensitivity of T cells in mice. SRG3 associates with the GC receptor in the thymus, but rarely in the periphery. Transgenic overexpression of the SRG3 protein in peripheral T cells induces the formation of the complex and ren ders the cells sensitive to GC-induced apoptosis. Our results also show tha t blocking the formation of the SRG3-GC receptor complex with a dominant ne gative mutant form of SRG3 decreases GC sensitivity in thymoma cells. In ad dition, mice overexpressing the SRG3 protein appear to be much more suscept ible to stress-induced deletion of peripheral T cells than normal mice, whi ch may result in an immunosuppressive state in an animal.