Cyclosporin A and dexamethasone suppress T cell responses by selectively acting at distinct sites of the triggering process.

Abstract The mechanism by which autogenic lectins induce proliferation in murine T cells has recently been dissected into two major events: a rapid, accessory cell-independent acquisition of responsiveness to growth factors, and an accessory cell-dependent elaboration of T cell growth factors (TCGF) occurring later in time. Within this background, the mode of action by which two different immunosuppressive drugs, namely, cyclosporin A and dexamethasone, inhibit T cell responses was studied. It was shown that cyclosporin A inhibits the lectin-dependent acquisition of responsiveness to growth factors in resting T cells at concentrations that have no effect on the production of TCGF. Furthermore, cyclosporin A does not interfere with the proliferative responses of preformed blasts to TCGF at these concentrations, demonstrating that lack of responsiveness to TCGF is not due to nonspecific toxicity of the drug. In contrast, dexamethasone at pharmacologic concentrations (10-6 M) did not inhibit the acquisition of responsiveness to growth factors, whereas it drastically reduced TCGF production. Furthermore, dexamethasone also failed to interfere with the mitogenic activity of preformed TCGF on T cell blasts, indicating that T lymphocytes involved in mitogenic responses are insensitive to nontoxic concentrations of dexamethasone, both at the initiation of the responses and at later phases of proliferate activity. These results demonstrate the distinct sites of action for two drugs, providing further insight into the mechanisms of T lymphocyte physiology and developing present possibilities of controlled application of such drugs in clinical practice.