Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance

The mechanisms of allograft tolerance have been classified as deletion, ane rgy, ignorance and suppression/regulation. Deletion has been implicated in central tolerance(1), whereas peripheral tolerance has generally been ascri bed to clonal anergy and/or active immunoregulatory states(2). Here, we use d two distinct systems to assess the requirement for T-cell deletion in per ipheral tolerance induction. in mice transgenic for Bcl-x(L), T cells were resistant to passive cell death through cytokine withdrawal, whereas T cell s from interleukin-2-deficient mice did not undergo activation-induced cell death. Using either agents that block co-stimulatory pathways or the immun osuppressive drug rapamycin, which we have shown here blocks the proliferat ive component of interleukin-2 signaling but does not inhibit priming for a ctivation-induced cell death, we found that mice with defective passive or active T-cell apoptotic pathways were resistant to induction of transplanta tion tolerance. Thus, deletion of activated T cells through activation-indu ced cell death or growth factor withdrawal seems necessary to achieve perip heral tolerance across major histocompatibility complex barriers.