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

Nature Medicine volume 5, pages 1303–1307 (1999)Cite this article

Abstract

The mechanisms of allograft tolerance have been classified as deletion, anergy, ignorance and suppression/regulation. Deletion has been implicated in central tolerance1, whereas peripheral tolerance has generally been ascribed to clonal anergy and/or active immunoregulatory states2. Here, we used two distinct systems to assess the requirement for T-cell deletion in peripheral tolerance induction. In mice transgenic for Bcl-xL, 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.

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Figure 1: Bcl-xL expression and survival in T cells of wild-type and Bcl-xL transgenic mice.
Figure 2: Resistance of Bcl-xL transgenic mice to CTLA4Ig.
Figure 3: Rapamycin blocks IL-2-driven T-cell proliferation, but does not inhibit Fas-mediated cell death.

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Acknowledgements

This work was supported by the National Kidney Foundation of America (X.C.L.), the Juvenile Diabetes Foundation (X.X.Z., T.B.S., M.H.S. and L.A.T.), the American Heart Association (L.A.T.) and the National Institutes of Health (AI-34665, AI-37691, AI-37798, AI-41521, AI-42298 and CA09140).

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Author notes

  1. A.D.W. and X.C.L. contributed equally to this paper.

Authors and Affiliations

  1. Department of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, 02215, Massachusetts , USA

    Xian Chang Li, Yongsheng Li, Xin Xiao Zheng & Terry B. Strom

  2. Department of Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Andrew D. Wells, Matthew C. Walsh, Zihao Wu, Aimin Tang & Laurence A. Turka

  3. Department of Pathology, University of Michigan, Ann Arbor, 48109, Michigan, USA

    Gabriel Nuñez

  4. & Department of Pathology, LeukoSite Inc., Harvard Medical School, Cambridge, 02142 , Massachusetts, USA

    Wayne W. Hancock

  5. Department of Medicine, Brigham and Women's Hospital Harvard Medical School, Boston, 02115, Massachusetts, USA

    Mohamed Sayegh

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  1. Andrew D. Wells
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Correspondence to Terry B. Strom or Laurence A. Turka.

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Wells, A., Li, X., Li, Y. et al. Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance. Nat Med 5, 1303–1307 (1999). https://doi.org/10.1038/15260

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