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- Title
Targeting DEC-205<sup>−</sup>DCIR2<sup>+</sup> dendritic cells promotes immunological tolerance in proteolipid protein-induced experimental autoimmune encephalomyelitis.
- Authors
Tabansky, Inna; Keskin, Derin B.; Watts, Deepika; Petzold, Cathleen; Funaro, Michael; Sands, Warren; Wright, Paul; Yunis, Edmond J.; Najjar, Souhel; Diamond, Betty; Cao, Yonghao; Mooney, David; Kretschmer, Karsten; Stern, Joel N. H.
- Abstract
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 (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 αDCIR2-PLP139–151 fusion antibody (Ab) depended on an immature state of targeted DCIR2+ DCs. The mechanism of αDCIR2-PLP139–151 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.
- Subjects
PROTEOLIPIDS; DENDRITIC cells; ENCEPHALOMYELITIS; CENTRAL nervous system diseases; AUTOIMMUNE diseases
- Publication
Molecular Medicine, 2018, Vol 24, Issue 1, pN.PAG
- ISSN
1076-1551
- Publication type
Article
- DOI
10.1186/s10020-018-0017-6