iPSC-Derived Regulatory Dendritic Cells Inhibit Allograft Rejection by Generating Alloantigen-Specific Regulatory T Cells
Liver-derived dendritic cell (DC) progenitors propagated in liquid culture in granulocyte/macrophage colony-stimulating factor exhibit low levels both of cell surface MHC class II antigens and of counter-receptors for CTLA-4/CD28. They fail to stimulate allogeneic T cells in mixed leukocyte cultures. To evaluate their in vivo functional significance, we determined their influence on survival of pancreatic islet allografts. Cultured B10.BR (H2k;I-E+) mouse liver-derived DC progenitors were injected (2 x 10(6) i.v.) into streptozotocin-diabetic B10 (H2b; I-E-) recipients 7 days before transplantation of pancreatic islets (700 IEq/mouse) from the same donor strain. No immunosuppressive agents were administered. Mean islet allograft survival time was prolonged from 15.3 days (in animals pretreated with syngeneic cells) to 30.3 days (P < 0.001) in mice pretreated with the donor-derived liver cells. In 20% of these animals, islet allograft survival exceeded 60 days. These data suggest that liver-derived DC progenitors may contribute both to the inherent tolerogenicity of the mouse liver and to its capacity to protect other allografts of the same donor strain from rejection.