Lymph Borne CD8α+ DCs Are Uniquely Able to Cross-Prime CD8+ T Cells with Intestinal Epithelial Cell-Derived Antigen

Cross-presentation of cellular antigen is crucial for priming CD8⁺ T cells, and generating immunity to intracellular pathogens- particularly viruses. It is unclear which intestinal phagocytes perform this function in vivo. We therefore examined dendritic cells (DCs) from intestinal lymph of IFABP-tOVA 232-4 mice, which express ovalbumin in small intestinal epithelial cells (IECs). Among lymph DCs (LDCs), only CD103⁺ CD11b^- CD8α⁺ DCs cross-present IEC-derived ovalbumin to CD8⁺ OT-I T cells. Similarly, in the mesenteric lymph nodes (MLN), cross-presentation of IEC-ovalbumin was limited to the CD11c⁺ MHCII^hi CD8α⁺ migratory DCs, but absent from all other subsets, including the resident CD8α^hi DCs. Crucially, delivery of purified CD8α⁺ LDCs, but not other LDC subsets, into the MLN subcapsular lymphatic sinus induced proliferation of ovalbumin-specific, gut-tropic CD8⁺ T cells in vivo. Finally, in 232-4 mice treated with R848, CD8α⁺ LDCs were uniquely able to cross-prime IFN-γ-producing CD8⁺ T cells and drive their migration to the intestine. These results clearly demonstrate that migrating CD8α⁺ intestinal DCs are indispensable for cross-presentation of cellular antigen and, in conditions of inflammation, for the initial differentiation of effector CD8⁺ T cells. They may therefore represent an important target for the development of anti-viral vaccinations.