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 CD11cCD8DEC-205 DCs.
METHODS: We employed a fusion between αDCIR2 antibodies and the highly encephalitogenic peptide 139-151 of myelin-derived proteolipid protein (PLP), to target CD11c CD8 DCs with a DEC-205-DCIR2 phenotype in vivo, and to substantially improve clinical symptoms in the PLP-induced model of experimental autoimmune encephalomyelitis (EAE).
RESULTS: Consistent with previous studies targeting other cell surface receptors, EAE protection mediated by αDCIR2-PLP fusion antibody (Ab) depended on an immature state of targeted DCIR2 DCs. The mechanism of αDCIR2-PLP 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 CD4Foxp3 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.
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