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

Andrew D. Wells, Xian Chang Li, Yongsheng Li, Matthew C. Walsh, Xin Xiao Zheng, Zihao Wu, Gabriel Nuñez, Aimin Tang, Mohamed Sayegh, Wayne W. Hancock, Terry B. Strom, Laurence A. Turka

Research output: Contribution to journalArticlepeer-review

528 Scopus citations


The mechanisms of allograft tolerance have been classified as deletion, anergy, ignorance and suppression/regulation. Deletion has been implicated in central tolerance, whereas peripheral tolerance has generally been ascribed to clonal anergy and/or active immunoregulatory states. Here, we used two distinct systems to assess the requirement for T-cell deletion in peripheral tolerance induction. In mice transgenic for Bcl-x(L), T cells were resistant to passive cell death through cytokine withdrawal, whereas T cells from interleukin-2-deficient mice did not undergo activation-induced cell death. Using either agents that block co-stimulatory pathways or the immunosuppressive drug rapamycin, which we have shown here blocks the proliferative component of interleukin-2 signaling but does not inhibit priming for activation-induced cell death, we found that mice with defective passive or active T-cell apoptotic pathways were resistant to induction of transplantation tolerance. Thus, deletion of activated T cells through activation-induced cell death or growth factor withdrawal seems necessary to achieve peripheral tolerance across major histocompatibility complex barriers.

Original languageEnglish (US)
Pages (from-to)1303-1307
Number of pages5
JournalNature Medicine
Issue number11
StatePublished - Nov 1999

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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