Involvement of dendritic cell subsets in the induction of oral tolerance and immunity

Dendritic cells (DCs) play a central role in the generation of immune responses in the intestine. I)Cs induce differentiation and tolerance of T cells, and may have a direct role in B cell switching to IgA. Four distinct. subsets of CD11c(+) DCs are present in murine Peyer's patches, which represent primary sites for the induction of mucosal T and B cell responses. Studies suggest that CD11b+ DCs or plasmacytoid DCs may be specialized for the induction of regulatory T cells, and CD8 alpha(+) DCs for the induction of clonal deletion in response to soluble oral antigen, while all DC subsets (including CD8 alpha(-)/CD11b(-) DCs) may be involved in responses to pathogens. We are currently using reovirus type-1 Lang (T1L) to explore the role of DC populations in mucosal immunity in vivo, as oral administration of live T1L to mice induces strong mucosal and systemic antiviral immune responses, whereas oral administration of inactivated T1L results in tolerance to viral proteins. We found that primary infection with T1L occurs in epithelial cells of the PP follicle-associated epithelium, but that CD8a-/CD11b- DCs in the subepithelial dome region (SED) are loaded with T1L antigens in the absence of active DC infection. At least a portion of this antigen is associated with cell fragments from apoptotic epithelial cells, demonstrating that SED DCs cross-present antigens from apoptotic epithelial cells. In vitro, in contrast to exposure to several TLR-ligands or anti-CD40, exposure to T1L does not activate DCs to mature or to produce cytokines, despite clear loading of the DCs with viral antigens. These data suggest that T1L is taken up by a "silent" receptor on DCs, and that the induction of immunity to T1L is dependent on signals from non-DCs following active viral infection that induce DC maturation. Thus, the decision between tolerance and immunity to inactive and live virus, respectively, likely depends on whether there is active infection of epithelial cells by T1L, which results in the elaboration of molecules, such as cytokines, that induce DC maturation.