Delta-like ligand 4 identifies a previously uncharacterized population of inflammatory dendritic cells that plays important roles in eliciting allogeneic T cell responses in …

K Mochizuki, F Xie, S He, Q Tong, Y Liu… - The Journal of …, 2013 - journals.aai.org
K Mochizuki, F Xie, S He, Q Tong, Y Liu, I Mochizuki, Y Guo, K Kato, H Yagita, S Mineishi…
The Journal of Immunology, 2013journals.aai.org
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 (Dll4
high) inflammatory dendritic cells (i-DCs) play important roles in eliciting allogeneic T cell …
Abstract
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 (Dll4 high) inflammatory dendritic cells (i-DCs) play important roles in eliciting allogeneic T cell responses. Host-type Dll4 high 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, Dll4 high 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 (Dll4 low) i-DCs were CD11c+ B220− PDCA-1−, and had low levels of Jagged1. In vitro assays showed that Dll4 high i-DCs induced significantly more IFN-γ–and IL-17–producing effector T cells (3-and 10-fold, respectively) than Dll4 low 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 Dll4 high i-DCs represent a previously uncharacterized i-DC population distinctive from steady state DCs and Dll4 low i-DCs. Furthermore, Dll4 and Dll4 high i-DCs may be beneficial targets for modulating allogeneic T cell responses, and could facilitate the discovery of human counterparts of mouse Dll4 high i-DCs.
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