Targeting DEC-205 − DCIR2 + dendritic cells promotes immunological tolerance in proteolipid protein-induced experimental autoimmune encephalomyelitis

Background Dendritic cells (DC) induce adaptive responses against foreign antigens, and play an essential role in maintaining peripheral tolerance to self-antigens. Therefore they are involved in preventing fatal autoimmunity. Selective delivery of antigens to immature DC via the endocytic DEC-205 receptor on their surface promotes antigen-specific T cell tolerance, both by recessive and dominant mechanisms. We provide evidence that the induction of antigen-specific T cell tolerance is not a unique property of CD11c + CD8 + DEC-205 + DCs. Methods We employed a fusion between αDCIR2 antibodies and the highly encephalitogenic peptide 139–151 of myelin-derived proteolipid protein (PLP 139–151 ), to target CD11c + CD8 - DCs with a DEC-205−DCIR2 + phenotype in vivo, and to substantially improve clinical symptoms in the PLP 139–151 -induced model of experimental autoimmune encephalomyelitis (EAE). Results Consistent with previous studies targeting other cell surface receptors, EAE protection mediated by αDCIR2-PLP 139–151 fusion antibody (Ab) depended on an immature state of targeted DCIR2 + DCs. The mechanism of αDCIR2-PLP 139–151 mAb function included the deletion of IL-17- and IFN-γ-producing pathogenic T cells, as well as the enhancement of regulatory T (Treg) cell activity. In contrast to the effect of αDEC-205 + fusion antibodies, which involves extrathymic induction of a Foxp3 + Treg cell phenotype in naïve CD4 + Foxp3 - T cells, treatment of animals with DCIR2 + fusion antibodies resulted in antigen-specific activation and proliferative expansion of natural Foxp3 + Treg cells. Conclusions These results suggest that multiple mechanisms can lead to the expansion of the Treg population, depending on the DC subset and receptor targeted.