In autoimmune-prone NOD mice, altered DC subsets induce aberrant activation of CD4 T cells, yet DCIR2+ DCs can still induce tolerance. (BA15P.218)

Abstract

Abstract Stimulation of CD4+ T cells by antigen targeted in vivo to dendritic cells (DCs) in the absence of inflammation usually leads to tolerance. However, DCs are altered in autoimmune-prone mice such as non-obese diabetic (NOD) mice, a model for type 1 diabetes. We observed altered DC responses in NOD mice to innate immune stimuli such as CpG, which may alter the ability of these DCs to induce tolerance. In addition, determining which antigen presenting cell populations are capable of inducing tolerance in the context of chronic autoimmunity is critical for antigen-specific treatments for autoimmune disease. We recently reported that in NOD mice, DEC-205+ DCs induce effector responses, not tolerance, in autoreactive CD4+ T cells. We now show that DCIR2+ DCs, distinct from DEC-205+ DCs, can be tolerogenic in NOD mice. Beta cell antigen targeted via chimeric antibody to DCIR2+ DCs delays disease induction in a transfer model of type 1 diabetes. DCIR2+ DC stimulation induces partial deletion of autoreactive CD4+ T cells and remaining cells are unable to produce IFN-γ. These disparate T cell outcomes after targeting antigen to DEC-205+ or DCIR2+ DCs are underpinned by differential gene expression in antigen-specific T cells early after stimulation. In conclusion, we have characterized defects in DCs in NOD mice, and the resulting altered T cell responses with the goal of identifying ways to induce tolerance even in the context of autoimmunity.