Effect of FK506 treatment on allocytolytic T lymphocyte induction in vivo: differential effects of FK506 on L3T4+ and Ly2+ T cells.

Although FK506 has been widely investigated as a potent suppressor of organ allograft rejection in animals, little is known about the effect of FK506 on T cell responses to allografts in vivo. In the present study, we have studied the effect of FK506 on the induction of allocytolytic T lymphocyte using mice primed with alloantigens and treated with FK506. FK506 suppressed the CTL induction of spleen cells and peritoneal exudate cells (PEC) in a dose-dependent manner. Time-course kinetic studies indicated that the CTL activity was markedly dependent on the time of administration of FK506 to the mice. Lymphocytes from these FK506-treated animals were found to be reactivated upon exposure to the same alloantigens in a secondary mixed lymphocyte culture (MLC). Furthermore, FK506 was shown to have a differential effect on the activation of helper (L3T4+) and cytotoxic (Ly2+) T cell subpopulations. L3T4+ T cells from the mice primed with alloantigens and treated with FK506 had normal helper activity in the generation of CTL in MLC, whereas Ly2+ T cells from these mice were profoundly suppressed CTL activity upon reexposure to the same alloantigens in a secondary MLC. Exogenous IL-2 or L3T4+ T cells could overcome the immunosuppressive effect of FK506 on the CTL induction of Ly2+ T cells in a secondary MLC. Finally, we have demonstrated that this FK506 effect appeared to be antigen nonspecific since Ly2+ T cells from alloprimed FK506-treated mice failed to induce CTL against the third-party alloantigens as well as the same alloantigens in a secondary MLC.