title: Donor-lymphocyte infusion induces transplantation tolerance by activating systemic and graft-infiltrating double-negative regulatory T cells.
abstract: Donor-lymphocyte infusion (DLI) before transplantation can lead to specific tolerance to allografts in mice, nonhuman primates, and humans. We and others have demonstrated a role for regulatory T cells in DLI-induced, donor-specific transplantation tolerance, but it is not known how regulatory T cells are activated and where they execute their function. In this study, we observed, in both transgenic and normal mice, that DLI before transplantation is required for activation of alphabeta-T-cell-receptor-positive, CD3(+)CD4(-)CD8(-) double-negative (DN) regulatory T cells in the periphery of recipient mice. More interestingly, DLI induced DN regulatory T cells to migrate preferentially to donor-specific allogeneic skin grafts and to form a majority of graft-infiltrating T cells in accepted skin allografts. Furthermore, both recipient-derived peripheral and graft-infiltrating DN T cells were able to suppress and kill antidonor CD8(+) T cells in an antigen-specific manner. These data indicate that DLI may induce donor-specific transplantation tolerance by activating recipient DN regulatory T cells in the periphery and by promoting migration of regulatory T cells to donor-specific allogeneic skin grafts. Our results also show that DN regulatory T cells can eliminate antidonor T cells both systemically and locally, a finding suggesting that graft-infiltrating T cells can be beneficial to graft survival.
authors.affiliation: Department of Laboratory Medicine, Multi Organ Transplantation Program, Toronto General Research Institute, University Health Network, University of Toronto, 101 College Street, Toronto, Ontario, Canada M5G 2C4.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Young
authors.forename: Liming
authors.initials: L
authors.lastname: Yang
authors.forename: M James
authors.initials: MJ
authors.lastname: Phillips
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002465:Cell Movement; D003433:Crosses, Genetic; D003602:Cytotoxicity, Immunologic; D006082:Graft Enhancement, Immunologic; D006085:Graft Survival; D006183:H-2 Antigens / Q000276:immunology; D007108:Immune Tolerance; D008213:Lymphocyte Activation; D017710:Lymphocyte Transfusion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016038:Skin Transplantation / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D014019:Tissue Donors; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D006183:H-2 Antigens