title: 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 hemopoietic stem cell transplantation.
abstract: 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.
authors.affiliation: Department of Hematology/Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Li
authors.forename: Lauren T
authors.initials: LT
authors.lastname: Southerland
authors.forename: Ying
authors.initials: Y
authors.lastname: Lu
authors.forename: Kataryna A
authors.initials: KA
authors.lastname: Darlak
authors.forename: Cynthia R
authors.initials: CR
authors.lastname: Giver
authors.forename: Douglas W
authors.initials: DW
authors.lastname: McMillin
authors.forename: Wayne A C
authors.initials: WA
authors.lastname: Harris
authors.forename: David L
authors.initials: DL
authors.lastname: Jaye
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Waller
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D001854:Bone Marrow Cells / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000276:immunology*; D006082:Graft Enhancement, Immunologic / Q000379:methods; D020544:Graft vs Leukemia Effect / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D007519:Isoantigens / Q000008:administration & dosage / Q000096:biosynthesis / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation
chemical_list: D007519:Isoantigens