IRF8-dependent DCs play a key role in the regulation of CD8 T cell responses to epithelialderived antigen in the steady state but not in inflammation

Along the process of epithelial self-renewal, antigens derived from apoptotic intestinal epithelial cells(IECs) are taken up by antigen presenting cells (APCs), transported to the gut-draining lymph nodesand cross-presented to CD8 T cells. In steady state, rapid tolerization of CD8 T cells reactive towards epithelial-derived antigens is crucial to maintain tissue homeostasis. In contrast, infection of IECs by intracellular pathogens requires induction of cytotoxic CD8 T cells (CTLs) towards epithelialassociated, pathogen-derived antigens. Currently, little is known about the regulation of CD8 T cells by intestinal APCs in these two different contexts. Since IRF8-dependent dendritic dells (IRF8-DCs) have superior cross-presenting capabilities, we aimed to investigate their role in this process. IFABP-tOva mice, expressing the model-antigen Ovalbumin (Ova) in IECs, were used as recipients to set up chimeras using either CD11c-cre.Irf8^fl/fl bone marrow, which cannot generate IRF8-DCs, or crenegative Irf8^fl/fl control bone marrow. Whereas transfer of Ova-specific CD8 T cells (OT-I cells) tosteady state control chimeras resulted in their rapid tolerization, OT-I cells transferred to CD11ccre.Irf8^fl/fl chimeras spontaneously developed into CTLs, causing epithelial destruction and intestinal inflammation. However, when the TLR7-ligand R848 was applied as an inflammatory trigger mimicking viral infection in addition to OT-I transfer, expansion of CTLs occurred at similar rates in both, CD11ccre.Irf8^fl/fl and control chimeras. Taken together, this demonstrates that IRF8-DCs are crucial for therapid tolerization of CD8 T cells reactive towards epithelial-derived antigen in steady state, but are notessential for the induction of CTLs in an inflammatory setting such as found in infection.