title: Requirement for T-cell apoptosis in the induction of peripheral transplantation tolerance.
abstract: 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-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.
authors.affiliation: Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: A D
authors.initials: AD
authors.lastname: Wells
authors.forename: X C
authors.initials: XC
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: M C
authors.initials: MC
authors.lastname: Walsh
authors.forename: X X
authors.initials: XX
authors.lastname: Zheng
authors.forename: Z
authors.initials: Z
authors.lastname: Wu
authors.forename: G
authors.initials: G
authors.lastname: Nuñez
authors.forename: A
authors.initials: A
authors.lastname: Tang
authors.forename: M
authors.initials: M
authors.lastname: Sayegh
authors.forename: W W
authors.initials: WW
authors.lastname: Hancock
authors.forename: T B
authors.initials: TB
authors.lastname: Strom
authors.forename: L A
authors.initials: LA
authors.lastname: Turka
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D017209:Apoptosis / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D060908:CTLA-4 Antigen; D002455:Cell Division; D005434:Flow Cytometry; D006085:Graft Survival / Q000276:immunology*; D018796:Immunoconjugates; D051379:Mice; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D014181:Transplantation Immunology; D051020:bcl-X Protein
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; C494812:Bcl2l1 protein, mouse; D018106:CD28 Antigens; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D000069594:Abatacept