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 alpha DCIR2 antibodies and the highly encephalitogenic peptide 139-151 of myelin-derived proteolipid protein (PLP139-151), to target CD11c(+)CD8(-) DCs with a DEC-205-DCIR2(+) phenotype in vivo, and to substantially improve clinical symptoms in the PLP139-151-induced model of experimental autoimmune encephalomyelitis (EAE). Results: Consistent with previous studies targeting other cell surface receptors, EAE protection mediated by alpha DCIR2-PLID139-151 fusion antibody (Ab) depended on an immature state of targeted DCIR2(+) DCs. The mechanism of alpha DCIR2-PLP139-151 mAb function included the deletion of IL-17- and IFN-gamma-producing pathogenic T cells, as well as the enhancement of regulatory T (Treg) cell activity. In contrast to the effect of alpha DEC-205(+) fusion antibodies, which involves extrathymic induction of a Foxp3(+) Treg cell phenotype in naive 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.