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

NOD CD8+ DCs express increased CD40; targeting of autoantigen to these cells induces Th1 responses, not tolerance, unless CD40/CD40L interactions are blocked. 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.