Targeting of proteins to DEC-205 through chimeric antibody constructs causes clonal deletion or anergy of antigen-specific CD4+ and CD8+ T cells in immunologically normal mice. In NOD mice, a mouse model for autoimmune diabetes, we previously have shown that beta cell-specific CD8+ T cells can be depleted by anti-DEC antigen treatment (Mukhopadhaya A, et al. PNAS 2008). Using DEC-205 targeting, we have now determined that in autoimmune NOD mice, CD8 DCs are not able to induce CD4+ T cell tolerance. Instead targeting cognate antigen to DEC205+ DCs induces expansion and IFN gamma production in the autoreactive CD4 T cells. We have shown that CD40/CD40L interactions are one pathway that is important in this setting: when a blocking antibody specific for anti-CD40L was given with anti-DEC-205 antigen, T cell responses were more tolerogenic (less expansion and IFN gamma production). This work was published this year in the Journal of Leukocyte Biology. CD11b+ dendritic cells express DCIR2 on their surface, and antibodies specific for DCIR2 can be used to target antigens to this DC subset. We have measured BDC2.5 TCR transgenic T cell responses in NOD mice after stimulation in vivo with anti-DCIR2-targeted BDC peptide. In contrast to the responses elicited by DEC205+ DCs, DCIR2+ DCs are able to induce a more tolerogenic response, characterized by less expansion, increased apoptosis and less IFN-gamma even in this chronic autoimmune context. In addition, anti-DCIR2-targeted BDC peptide inhibits diabetes development. By comparing gene expression in beta cell-specific T cells early after in vivo stimulation with either DEC205+ or DCIR2+ DCs, we have identified genes that are expressed at higher levels in T cells stimulated with DCIR2+ DCs.
