Effect of cyclosporin A on T cell function in vitro: the mechanism of suppression of T cell proliferation depends on the nature of the T cell stimulus as well as the differentiation state of the responding T cell.

We have studied the effects of the immunosuppressive agent cyclosporin A (CY A) on T cell activation in the guinea pig both in the presence and in the absence of exogenous interleukin 2 (IL 2). CY A suppressed T cell activation by the mitogen, concanavalin A, by blocking IL 2 production and not by blocking the induction of IL 2 receptors. In contrast, the primary T cell proliferative responses to self-Ia antigens in the syngeneic mixed leukocyte reaction (SMLR) and to trinitrophenyl-modified syngeneic macrophages were blocked by CY A and this suppressive effect could not be corrected by addition of exogenous IL 2. T cells primed to syngeneic stimulator cells in the presence of CY A failed to develop IL 2 responsiveness even in the presence of exogenous IL 2, suggesting that CY A directly blocked induction of IL 2 receptors on the responding T cell population. In contrast, the secondary SMLR was suppressed by CY A in the absence of IL 2, but was normal when IL 2 was added to the cultures. CY A completely blocked the primary allogeneic MLR but this inhibitory effect could be reversed when exogenous IL 2 was added to the cultures. Moreover, in the presence of exogenous IL 2, CY A had no effect on the development of IL 2 responsiveness by alloreactive T cells. In addition, CY A induced a population of radiosensitive cells with suppressor activity for the primary MLR. Thus, in the guinea pig, CY A inhibits Ti cell activation both by blocking IL 2 production as well as by inhibiting the induction of IL 2 responsiveness. These two effects occur in the same range of CY A concentrations and are differentially dominant depending on the nature of the stimulating signal and the differentiation state of the responding T cell.