title: Double negative Treg cells promote nonmyeloablative bone marrow chimerism by inducing T-cell clonal deletion and suppressing NK cell function.
abstract: The establishment of immune tolerance and prevention of chronic rejection remain major goals in clinical transplantation. In bone marrow (BM) transplantation, T cells and NK cells play important roles for graft rejection. In addition, graft-versus-host-disease (GVHD) remains a major obstacle for BM transplantation. In this study, we aimed to establish mixed chimerism in an irradiation-free condition. Our data indicate that adoptive transfer of donor-derived T-cell receptor (TCR) αβ(+) CD3(+) CD4(-) CD8(-) NK1.1(-) (double negative, DN) Treg cells prior to C57BL/6 to BALB/c BM transplantation, in combination with cyclophosphamide, induced a stable-mixed chimerism and acceptance of C57BL/6 skin allografts but rejection of third-party C3H (H-2k) skin grafts. Adoptive transfer of CD4(+) and CD8(+) T cells, but not DN Treg cells, induced GVHD in this regimen. The recipient T-cell alloreactive responsiveness was reduced in the DN Treg cell-treated group and clonal deletions of TCRVβ2, 7, 8.1/2, and 8.3 were observed in both CD4(+) and CD8(+) T cells. Furthermore, DN Treg-cell treatment suppressed NK cell-mediated BM rejection in a perforin-dependent manner. Taken together, our results suggest that adoptive transfer of DN Treg cells can control both adoptive and innate immunities and promote stable-mixed chimerism and donor-specific tolerance in the irradiation-free regimen.
authors.affiliation: The Multi-Organ Transplant Program, London Health Sciences Centre, London, Ontario, Canada.
authors.forename: Ye
authors.initials: Y
authors.lastname: Su
authors.forename: Xuyan
authors.initials: X
authors.lastname: Huang
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Min
authors.forename: Ziqin
authors.initials: Z
authors.lastname: Yin
authors.forename: Anthony M
authors.initials: AM
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; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D046528:Chimerism / Q000187:drug effects*; D017637:Clonal Deletion / Q000187:drug effects / Q000276:immunology*; D003520:Cyclophosphamide / Q000627:therapeutic use; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000276:immunology; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D054353:Perforin / Q000276:immunology; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016038:Skin Transplantation / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D007166:Immunosuppressive Agents; D011948:Receptors, Antigen, T-Cell; D054353:Perforin; D003520:Cyclophosphamide