CD8 dendritic cell-mediated tolerance of autoreactive CD4 T cells is deficient in NOD mice and can be corrected by blocking CD40L

DCs are important mediators of peripheral tolerance for the prevention of autoimmunity. Chimeric αDEC-205 antibodies with attached antigens allow in vivo antigen-specific stimulation of T cells by CD8+ DCs, resulting in tolerance in nonautoimmune mice. However, it is not clear whether DC-mediated tolerance induction occurs in the context of ongoing autoimmunity. We assessed the role of CD8+ DCs in stimulation of autoreactive CD4+ T cells in the NOD mouse model of type 1 diabetes. Targeting of antigen to CD8+ DCs via αDEC-205 led to proliferation and expansion of β-cell specific BDC2.5 T cells. These T cells also produced IL-2 and IFN-γ and did not up-regulate FoxP3, consistent with an activated rather than tolerant phenotype. Similarly, endogenous BDC peptide-reactive T cells, identified with I-Ag7 tetramers, did not become tolerant after antigen delivery via αDEC-205: no deletion or Treg induction was observed. We observed that CD8+ DCs from NOD mice expressed higher surface levels of CD40 than CD8+ DCs from C57BL/6 mice. Blockade of CD40–CD40L interactions reduced the number of BDC2.5 T cells remaining in mice, 10 days after antigen targeting to CD8 DCs, and blocked IFN-γ production by BDC2.5 T cells. These data indicate that the ability of autoreactive CD4+ T cells to undergo tolerance mediated by CD8+ DCs is defective in NOD mice and that blocking CD40–CD40L interactions can restore tolerance induction.