FK506 AUGMENTS ACTIVATION-INDUCED PROGRAMMED CELL-DEATH OF T-LYMPHOCYTES IN-VIVO

FK506 is an immunosuppressive drug that inhibits T cell receptor-mediated signal transduction, This drug can induce immunological tolerance in allograft recipients, In this study, we investigated the in vivo effects of FK506 on T cell receptor-mediated apoptosis induction. Injection of antiCD3 antibody (Ab) in mice resulted in the elimination of CD4(+) CD8(+) thymocytes by DNA fragmentation. FK506 treatment significantly augmented thymic apoptosis induced by in vivo anti-CD3 Ab administration, Increased thymic apoptosis resulted in the disappearance of CD4(+) CD8(+) thymocytes after anti-CD3 Ab/FK506 treatment, DNA fragmentation triggered by FK506 was induced exclusively in antigen-stimulated T cells, since enhanced DNA fragmentation induced by in vivo staphylococcal enterotoxin B (SEE) injection was confirmed in SEE-reactive V beta 8(+) thymocytes but not in SEB-nonreactive V beta 6(+) thymocytes. In addition to thymocytes, mature peripheral T cells also die by activation-induced programmed cell death, A similar effect of FK506 on activation-induced programmed cell death was observed in SEE-activated peripheral spleen T cells, In contrast, cyclosporin A treatment did not enhance activation-induced programmed cell death of thymocytes and peripheral T cells. Apoptosis is required for the generation and maintenance of self-tolerance in the immune system, Our findings suggest that FK506-triggered apoptosis after elimination of antigen-activated T cells may represent a potential mechanism of the immunological tolerance achieved by FK506 treatment.