Establishment of nonmyeloablative bone marrow chimerism by double negative Treg cells through inducing T cell clonal deletion and suppressing NK cell function (126.1)

Abstract

Abstract In bone marrow transplantation, T cells and NK cells play important role for graft rejection. In addition, graft-versus-host-disease and establishment of stable chimeric states without complete marrow ablation remain as major obstacles post bone marrow transplantation. In this study, we aimed to establish mixed chimerism in a non-irradiation condition. Our data indicate that adoptive transfer of donor-derived TCRαβ+CD3+CD4-CD8-NK1.1-(double negative, DN) Treg cells prior to C57BL/6 to BALB/c bone marrow transplantation, in combination with cyclophosphamide but not cyclosporine, FK506, or rapamycin, established stable mixed chimerism that led to acceptance of C57BL/6 skin allografts and rejection of 3rd party C3H skin grafts. Adoptive transfer of CD4+ and CD8+ T cells, but not DN-Treg cells, induced graft-versus-host diseases in this regimen. The recipient T cell alloreacitve responsiveness was reduced in the DN-Treg cell-treated group and T cell receptor Vβ2, Vβ7 and Vβ8 clonal deletions were observed in both CD4+ and CD8+ T cells. Furthermore, DN-Treg cell treatment suppressed NK cell-mediated donor bone marrow rejection in perforin-dependent manner. Taken together, our results suggest that adoptive transfer of DN-Treg cells can control both adoptive and innate immunity and promote a stable mixed chimerism and donor-specific tolerance in the non-irradiation regimen.