title: Donor double-negative Treg promote allogeneic mixed chimerism and tolerance.
abstract: Bone marrow (BM) transplantation is an efficient approach to develop donor-specific tolerance and prevent chronic rejection. Allogeneic BM transplantation is limited by donor T cell-mediated graft-versus-host disease, requirement of cytoreduction and high numbers of BM cells. In addition of these drawbacks, recent studies demonstrate that not only T cells, but also NK cells can mediate BM rejection, and long-term mixed chimerism depends on NK cell tolerance. Thus, NK cell is another potential barrier against engraftment of BM and an important target in efforts to induce transplant tolerance. We have previously identified a novel type of Treg with the phenotype TCRalphabeta+CD3+CD4-CD8- (double-negative, DN). We and others have demonstrated that DN-Treg can effectively suppress anti-donor T cell responses. In this study, we found that donor-derived DN-Treg can suppress NK cell-mediated allogeneic BM graft rejection in both parent-to-F1 and fully MHC-mismatched BM transplantation models. Perforin and FasL in DN-Treg play important roles in the suppression of NK cells. Furthermore, adoptive transfer of DN-Treg can promote a stable mixed chimerism and donor-specific tolerance without inducing graft-versus-host disease. These results demonstrate a potential approach to control innate immune responses and promote allogeneic BM engraftment.
authors.affiliation: Multi-Organ Transplant Program, London Health Sciences Centre, London, Ontario, Canada.
authors.forename: Kathy M
authors.initials: KM
authors.lastname: He
authors.forename: Yuexia
authors.initials: Y
authors.lastname: Ma
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Min
authors.forename: Robert
authors.initials: R
authors.lastname: Zhong
authors.forename: Anthony
authors.initials: A
authors.lastname: Jevnikar
authors.forename: Zhu-Xu
authors.initials: ZX
authors.lastname: Zhang
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D017252:CD3 Complex / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D053222:Fas Ligand Protein / Q000172:deficiency / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology; D006183:H-2 Antigens / Q000276:immunology; D007108:Immune Tolerance; D016130:Immunophenotyping; D007694:Killer Cells, Natural / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D052899:Pore Forming Cytotoxic Proteins / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014019:Tissue Donors; D018183:Transplantation Chimera / Q000276:immunology; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D017252:CD3 Complex; D015704:CD4 Antigens; D016827:CD8 Antigens; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006183:H-2 Antigens; D052899:Pore Forming Cytotoxic Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta; C483886:perforin, mouse