In vivo data suggest that monocytes participate critically in cross-presentation, but other data suggest that lymph node resident dendritic cells (DCs) mainly cross-present. Here, we utilized a three-dimensional model of a blood vessel wall that endogenously supports DC development from human monocytes, and we incorporated dying autologous cells in the subendothelial matrix of the model. Flu-infected dying cells promoted monocytes to become mature DCs and cross-present cell-associated Ags for the activation of CTLs. Similar responses were induced by loading the dying cells with the TLR7/8 ligand ssRNA, whereas dying cells loaded with TLR3 ligand were less efficient. Monocyte-derived DCs that developed in this model cross-presented Ag to T cells efficiently regardless of whether they engulfed detectable amounts of labeled dying cells. Unexpectedly, the monocyte-derived cells that directly engulfed dying cells in vitro were not the major APCs stimulating CD8+ lymphocytes. Instead, bystander DCs acquired more robust capacity to cross-prime through receipt of MHC class I/peptide from the phagocytic, monocyte-derived cells. In mice, lymph node-homing monocyte-derived DCs processed Ags from engulfed cells and then transferred MHC class I/peptide complexes to confer cross-priming capacity to MHC class I-deficient lymph node resident CD8α+ DCs. Thus, natural or synthetic TLR7/8 agonists contained within dying cells promote the conversion of monocytes to DCs with capacity for cross-presentation and for "cross-dressing" other DCs. These data reveal a way in which migratory monocyte-derived DCs and other DCs, like lymph node resident DCs, both mediate cross-presentation.