Targeting DEC-205^-DCIR2⁺ dendritic cells promotes immunological tolerance in proteolipid protein-induced experimental...

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.

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).

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.

These results suggest that multiple mechanisms can lead to the expansion of the Treg population, depending on the DC subset and receptor targeted.