Abstract IL-2-independent CD8+ rat x BW5147 T cell hybridomas are highly sensitive to treatment with 10(-6) M dexamethasone. This glucocorticoid analog induces a rapid DNA fragmentation with a pattern similar to that observed during glucocorticoid-induced killing of mouse thymocytes, which suggests the activation of a similar specific endonuclease. Among these hybrids, we select variants expressing low affinity IL-2R, as measured by IL-2 binding assay and by the cell surface expression of the IL-2Rp55 Ag (rat CD25 recognized by OX-39 mAb). These OX-39+ IL-2 independent hybrids (named V type) are protected from the toxic action of dexamethasone by IL-2. The addition of IL-2 to V type cells induces the expression of a low number of high affinity IL-2R, which is strongly potentiated by the simultaneous addition of dexamethasone. Furthermore, dexamethasone is strongly synergistic with IL-2 in the induction of mRNA p55/IL-2R, which could be observed 6 h after the treatment. These data suggest that the utilization of the IL-2-R signaling pathway may induce an effective protection against glucocorticoid toxicity in mature T cells. Finally, we proved that the upregulation of IL-2R by IL-2 is strongly potentiated by glucocorticoids, which implies a new role for these agents in the immune system.