Graft-versus-host disease (GVHD) reflects an exaggerated inflammatory allogeneic T cell response in hosts receiving allogeneic hematopoietic stem cell transplantation (HSCT). Inhibition of pan-Notch receptor signaling in donor T cells causes reduction of GVHD. However, which Notch ligand(s) in what APCs is important for priming graft-versus-host reaction remains unknown. We demonstrate that δ-like ligand-4 (Dll4) and Dll4-positive (Dll4high) inflammatory dendritic cells (i-DCs) play important roles in eliciting allogeneic T cell responses. Host-type Dll4high i-DCs occurred in the spleen and intestine of HSCT mice during GVHD induction phase. These Dll4 high i-DCs were CD11c+B220+PDCA-1+, resembling plasmacytoid dentritic cells (pDCs) of naive mice. However, as compared with unstimulated pDCs, Dll4high i-DCs expressed higher levels of costimulatory molecules, Notch ligands Jagged1 and Jagged2, and CD11b, and produced more Ifnb and Il23 but less Il12. In contrast, Dll4-negative (Dll4low) i-DCs were CD11c+B2202PDCA-12, and had low levels of Jagged1. In vitro assays showed that Dll4high i-DCs induced significantly more IFNγ-and IL-17-producing effector T cells (3- and 10-fold, respectively) than Dll4low i-DCs. This effect could be blocked by anti-Dll4 Ab. In vivo administration of Dll4 Ab reduced donor-alloreactive effector T cells producing IFN-γ and IL-17 in GVHD target organs, leading to reduction of GVHD and improved survival of mice after allogeneic HSCT. Our findings indicate that Dll4high i-DCs represent a previously uncharacterized i-DC population distinctive from steady state DCs and Dll4low i-DCs. Furthermore, Dll4 and Dll4high i-DCs may be beneficial targets for modulating allogeneic T cell responses, and could facilitate the discovery of human counterparts of mouse Dll4high i-DCs.
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