In Vivo Expansion of Recipient DC Leads to Deletion of Donor Alloreactive CD8+ T Cells and Is an Alternative to Post-Transplant Cyclophosphamide for the Prevention of Graft-Versus-Host Disease after BMT

Allogeneic bone marrow transplantation (BMT) provides curative therapy for leukemia via immunological graft-versus-leukemia (GVL) effects. In practice, this must be balanced against graft-versus-host disease (GVHD) and opportunistic infection. We have investigated the role of recipient dendritic cells (DC) in the control of MHC class I restricted T cell responses after BMT. We first used the C3H.Sw → B6 miHA mismatched model of mouse BMT, with lethally irradiated B6.CD11c.DOG recipients (diphtheria toxin receptor, ovalbumin and GFP driven off the CD11c promoter) such that recipient DC can be deleted by diphtheria toxin, in combination with B6-derived MLL-AF9 induced primary acute myeloid leukemia to model clinical relapse. Depletion of recipient DC resulted in improved leukemic control (median survival 43 vs 31 days, P <0.001). The use of IRF8-/- BMT recipients (CD8α+ DC subset absent) confirmed that recipient CD8α+ DC were critical for regulating these GVL effects (median survival 43 vs 34 days, P = 0.0005). We confirmed that this accelerated relapse occurred as a consequence of recipient DC-induced donor T cell apoptosis resulting in a profound contraction of the donor T cell compartment. Using the same depletion strategies in an antigen-specific model (donor OT-I T cells, B6.CD11c.DOG x DBA/2 F1 recipients) we confirmed that recipient DC invoked effector donor CD8+ T cell hyperactivation, differentiation and apoptosis (Annexin V+ OT-I; 52.4% vs. 23.9% in DC replete vs. depleted recipients, P = 0.01).