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 anti-CD3 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 (SEB) injection was confirmed in SEB-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 SEB-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.
Migita
K
K
First Department of Internal Medicine, Nagasaki University School of Medicine, Japan.
Eguchi
K
K
Kawabe
Y
Y
Tsukada
T
T
Mizokami
A
A
Nagataki
S
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D017252:CD3 Complex / Q000276:immunology; D016572:Cyclosporine / Q000494:pharmacology; D004249:DNA Damage; D004768:Enterotoxins / Q000276:immunology / Q000494:pharmacology; D007108:Immune Tolerance / Q000187:drug effects*; D008213:Lymphocyte Activation / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000502:physiology*; D018089:Superantigens / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D004768:Enterotoxins; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens; C031818:enterotoxin B, staphylococcal; D016572:Cyclosporine; D016559:Tacrolimus