SYNERGISM BETWEEN THE CD3 ANTIGEN-DERIVED AND CD2 ANTIGEN-DERIVED SIGNALS - EXPLORATION AT THE LEVEL OF INDUCTION OF DNA-BINDING PROTEINS AND CHARACTERIZATION OF THE INHIBITORY ACTIVITY OF CYCLOSPORINE

We have demonstrated earlier that the crosslinkage of the CD3/TCR comp lex with the CD2 antigen results in the proliferation of normal human T cells. The effect of this synergism was perceptible at the level of induction of the IL-2 gene, a process critical for T cell growth. To f urther understand the molecular and nuclear basis for this synergism, we have explored the induction of DNA-binding proteins in highly purif ied normal human T cells signaled via the CD3 and/or CD2 proteins. The effect of transmembrane signaling of T cells with ionomycin, and/or s n-1,2 dioctanoyl glycerol, was also determined. The emergence of nucle ar binding proteins was investigated using interleukin-2 sequence spec ific oligonucleotide probes in the electrophoretic mobility shift assa y. Our studies demonstrate for the first time that CD3 antigen-derived signals and CD2 antigen-derived signals are synergistic in inducing t he emergence of transcription factors that bind to the NF-AT1, AP-1, a nd NF-kB sites located in the promoter/enhancer region of the IL-2 gen e. Moreover, cyclosporine, at concentrations readily accomplished in c linical practice, was found to inhibit the emergence of these DNA-bind ing proteins in normal human T cells signaled via cell surface protein s implicated in antigen-dependent T cell activation and in T cells sti mulated by mobilization of cellular calcium and activation of protein kinase C.