Recipient’s monocyte-derived dendritic cells and macrophages play key roles in acute cardiac allograft rejection (TRAN3P.864)

Donor-derived dendritic cells (DCs) migrating out of allografts into recipient lymphoid organs, and recipient lymphoid-resident DCs within draining lymphoid organs are classically considered the instigators of acute rejection in heart transplants. However, the role of the more recently described CD11cint CD11b+ Ly6C+ monocyte-derived (mo) DCs in acute allograft rejection is unknown. We demonstrate in a mouse model that cardiac allografts are infiltrated by recipient mo-DCs and mo-macrophages, each originating from different subsets of blood monocytes, within one week of transplantation. Graft-infiltrating mo-DCs are the main producers of IL-12p70 and exhibit potent T cell allo-stimulation and Th1 bias. Ablation of DCs after allo-sensitization correlates with reduced T cell proliferation and increased T cell death inside the graft, and prolonged transplant survival. Comparatively, graft-infiltrating mo-macrophages are far less efficient Ag-presenting cells, but release TNF-α and nitric oxide, the latter of which impairs T cell survival and promotes allograft survival. Our results indicate that both recipient mo-DCs and mo-macrophages play key roles during acute rejection within heart allografts, and that these cell subtypes, or potentially their blood monocyte precursors, could serve as therapeutic targets to prevent or treat acute rejection.