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.

Pharmacological inhibition of VIP signaling enhances antiviral immunity and improves survival in murine cytomegalovirus-infected allogeneic bone marrow transplant recipients

“…To explore VIP signaling blockade on immune responses to vaccination, we vaccinated B6→B10.BR allo-transplant recipients 13 with Lm-MCMV (containing the immuno-dominant M45 mCMV peptide 14 ) Recipients of WT allografts were treated with 7 days of PBS or VIPhyb starting 1 day before vaccination (day 1 28 posttransplant) followed by high-dose mCMV infection (1 3 We have previously shown that VIP-KO mice have more antiviral CD8 T-cells and enhanced antiviral cytolytic activity after mCMV infection. 8 The current study demonstrates that transplanting VIP-KO allografts or treatment with a VIP antagonist enhances donor-derived cellular antiviral immunity and improves survival without increasing GVHD in allo-BMT.…”

“…Preparation of BM cells and splenocytes from VIP-KO or WT B6 mice, and irradiation (11Gy) of CB6/F1 and B10BR recipient mice were performed as previously described. 8,12,13 On day 0, irradiated mice received 5 3 10 6 T-cell depleted BM (TCD-BM) cells with 0, 1 3 10 6 , 3 3 10 6 , or 8 3 10 6 donor splenocytes or 0.1 3 10 6 , 0.3 3 10 6 , or 1 3 10 6 purified donor T-cells via tail-vein injection. Donor chimerism in peripheral blood was determined 1-2 months posttransplant and was typically >95%.…”

IFN-γ and indoleamine 2,3-dioxygenase signaling between donor dendritic cells and T cells regulates graft versus host and graft versus leukemia activity

“…23,24 Using allogeneic MHC-mismatched HSCT (C57BL/63B10.BR) in mice harboring the T lymphoblastic leukemia cell line LBRM, we have reported previously that recipients transplanted with FACS-purified lineage Ϫ CD11c ؉ CD11b Ϫ DCs in combination with purified HSCs and T cells had better leukemia-free survival, higher numbers of IFN-␥-producing donor T-cells, as well as higher levels of serum IFN-␥ than mice transplanted with HSCs and T cells alone. 10 Here, we tested whether production of IFN-␥ by donor T cells was necessary for the improved leukemia-free survival using lineage Ϫ CD11c ؉ CD11b Ϫ PDCA1 ؉ B220 ؉ donor pre-pDCs. 10 Similar to the results of Yang et al, 25 transplantation of T cells from allogeneic IFN-␥ knockout (IFN-␥ Ϫ/Ϫ ) mice led to severe acute GVHD compared with recipients of T cells from wild-type mice.…”

“…3 Recently, using 2 allogeneic murine BMT models (C57BL/ 63B10.BR and C3H3C57BL/6), we showed that addition of donor bone marrow cells enriched for pre-pDCs to a graft composed of purified HSC and T cells significantly improved long-term leukemia-free survival without increasing GVHD compared with recipients of donor HSC and T cells. 10 Of note, higher numbers of IFN-␥-producing donor T cells were seen among recipients of pDCs. 10 The aim of the present work was to further define the mechanism by which donor pre-pDCs modulate the alloreactivity of donor T cells.…”

“…10 The aim of the present work was to further define the mechanism by which donor pre-pDCs modulate the alloreactivity of donor T cells. Based on the marked up-regulation of IFN-␥ in donor T cells cotransplanted with bone marrow enriched for pre-pDCs, 10,11 we hypothesized that IFN-␥-responsive genes in donor pre-pDCs might be involved in their immunomodulatory activity.Using highly purified populations of donor pre-pDCs, we observed that IFN-␥ signaling by donor T cells to donor pre-pDCs led to increased indoleamine-2,3-dioxygenase (IDO) expression in donor pDCs and that IDO production by donor pDCs suppressed the GVHD activity of donor T cells and changed the balance between regulatory and inflammatory donor T cells. These data support a new paradigm for immune regulation in allogeneic HSCT in which donor DCs first activate donor T cells and then subsequently limit GVHD through IDO-dependent modulation of inflammation.…”