In view of the importance of the IL-2 receptors in the expression of antiallograft immunity and the currently existing controversy regarding the effect of CsA on the induction of IL-2 receptors, we explored the effect of cyclosporine on the induction of interleukin-2 receptor alpha and beta in normal human T cells. The effect of CsA on the induction of IL-2 receptors was examined at the levels of mRNA expression (with the aid of the polymerase chain reaction), protein (by SDS-PAGE analysis of chemically crosslinked 125I-IL-2 membrane protein complexes and by FACS), and function (by Scatchard analysis of 125I-IL-2 binding to T cells). The T cells were signaled with sn-1,2-dioctanoylglycerol and ionomycin or with crosslinked anti-CD3 and anti-CD2 mAbs. Our experimental design revealed that (A) CsA inhibits the induction of IL-2 receptor alpha and beta in normal human T cells, (B) the inhibitory activity is realized by a direct effect on T cells, and (C) the inhibitory activity is detectable at the pretranslational level--CsA significantly reduced the induction of mRNA encoding IL-2 receptor alpha and IL-2 receptor beta. These observations together persuasively demonstrate the ability of CsA to interrupt the emergence of IL-2 receptors on the surface of normal human T cells.