The effects of immunosuppressive drugs on the regulation of activation-induced apoptotic cell death in thymocytes.

This study investigated the effects of immunosuppressive drugs on the regulation of thymocyte sensitivity to clonal deletion via programmed cell death, or apoptosis. We have previously shown that TcR/CD3 cross-linking and intracellular stimuli that mimic TcR/CD3 cross-linking induce apoptosis in many immature thymocytes in the presence, but not in the absence, of cyclosporine (CsA). We have interpreted those results to suggest that TcR/CD3-associated signals induce a CsA-sensitive mechanism that protects the cells from activation-induced apoptosis. In the present study, we compared the effects of CsA, FK506, and rapamycin (RAP) on the regulation of thymocyte apoptosis. Optimal concentrations of CsA and FK506 augmented apoptosis to similar levels. However, FK506 was approximately 100-fold more potent than CsA in thymocytes, which parallels the relative potencies of these drugs in inhibiting mitogen-induced proliferation of mature T cells. In contrast to CsA and FK506, RAP did not exhibit substantial apoptosis-augmenting activity. However, RAP interfered with the activity of FK506. This pattern mirrors that of RAP in TcR/CD3-mediated signaling pathways in mature T cells. Together these results provide evidence (1) that CsA, FK506, and RAP can act on immature thymocytes, (2) that the mechanisms by which the drugs affect mature and immature T cell responses are similar, and (3) that immunosuppressive drug therapy may affect not only mature peripheral T cells but also developing immature thymic T cells.