Activation Immune Polarization and Graft-versus-Leukemia Activity of Donor T-cells are Regulated by Specific Subsets of Donor Bone Marrow Antigen-Presenting Cells in Allogeneic Hematopoietic Stem Cell Transplantation

摘要

We investigated the roles of specific subsets of donor APCs purified from bone marrow in donor T cell activation and graft-vs-leukemia (GvL) activity in murine models of hemopoietic stem cell transplantation. Lineage⁻CD11c⁺ APC precursors were separated from donor bone marrow based on expression of CD11b. Transplanting lineage⁻CD11c⁺CD11b⁻ APC (CD11b⁻ APC) in combination with c-kit⁺Sca-1⁺lineage⁻ hemopoietic stem cells (HSC) and congenic donor T cells led to increased donor CD4⁺ and CD8⁺ T cell proliferation and higher donor T cell chimerism than with transplanting grafts containing HSC, T cells, and lineage⁻CD11c⁺CD11b⁺ APCs (CD11b⁺ APC), or grafts containing only HSC and T cells. Transplanting CD11b⁻ APCs induced Th1/type 1 cytotoxic T lymphocyte donor T cell immune polarization and enhanced GvL activity of donor T cells without increased graft-vs-host disease in both MHC- and minor histocompatibility Ag-mismatched murine hemopoietic stem cell transplantation models, whereas CD11b⁺ APCs led to Th2/type 2 cytotoxic T lymphocyte donor T cell immune polarization. Donor CD11b⁻ APCs were plasmacytoid dendritic cell progenitors (>90% CD317; PDCA-1⁺) and up-regulated CD80, CD86, and IL-12 during alloantigen presentation, whereas CD11b⁺ APCs expressed Gr-1 and up-regulated expression of programmed death ligands-1 and 2 after activation. These results are the first to show that manipulation of the content of donor APCs in allogeneic HSC grafts can regulate donor T cell immunity and enhance GvL without increasing graft-vs-host disease activity.