A NOVEL IMMUNOSUPPRESSANT, FTY720, INCREASES THE EFFICIENCY OF A SUPERANTIGEN-INDUCED PERIPHERAL T-CELL DELETION WHILE INHIBITING NEGATIVE SELECTION IN THE THYMUS

A novel immunosuppressant, FTY720, was generated by chemical modificat ion of ISP-I, an immunosuppressive compound purified from culture filt rates of Isaria sinclairii. FTY720 directly induces apoptotic cell dea th in lymphocytes, which is believed to be the mechanism by which this drug exerts its immunosuppressive effect. We examined the effect of F TY720 treatment on antigen-induced apoptotic cell death in peripheral T cells and thymocytes. A superantigen, staphylococcus enterotoxin B ( SEB), induces T-cell antigen receptor (TCR) V beta-specific apoptotic cell death in mature T cells in vivo. In this well-documented experime ntal system, FTY720 administration significantly enhanced the efficien cy of superantigen-induced T-cell deletion. We also determined that ap optotic cell death with DNA fragmentation induced in T-hybridoma cells after stimulation in vitro with anti-TCR antibodies was enhanced in t he presence of non-cytolytic doses of FTY720. In sharp contrast, negat ive selection of T cells in the thymus, another example of antigen-ind uced apoptosis, was found to be inhibited by FTY720 treatment. A rescu e effect was observed on clonal deletion in the H-Y-specific TCR alpha beta transgenic male thymus. In a chicken egg albumin (OVA)-specific TCR alpha beta transgenic system, OVA-induced apoptotic cell death of CD4(+)CD8(+) thymocytes was also inhibited by FTY720 injection. Thus, FTY720 increased the susceptibility of mature T cells to TCR-mediated apoptosis but decreased that of immature thymocytes. The results in th is report suggest that the potent immunosuppressive effect of FTY720 i s, in part, a result of the augmentation of effects on antigen-induced apoptosis in mature T cells, and that two distinct apoptotic cell dea th pathways are operating in mature and immature T cells.