We use chimeric antibodies to deliver antigens to specific DC subsets in vivo. Compared to responses elicited by DEC205+ DCs, DCIR2+ DCs are able to induce a more tolerogenic response in self-specific T cells, characterized by less expansion, increased apoptosis and less IFN-gamma even in this chronic autoimmune context. In addition, anti-DCIR2-targeted islet antigen 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 the more tolerogenic DCIR2+ DCs including the transcriptional regulator zbtb32. Overexpression of zbtb32 in T cells elicits a response similar to DCIR2 DC stimulation, with decreased expansion, IFN gamma production and inhibition of diabetes development. We are now characterizing NOD zbtb32 knockout mice we produced with CRISPR directly into the NOD background to determine what effect loss of this regulator has on T cell responses and diabetes.
