β‐Catenin stabilization in NOD dendritic cells increases IL‐12 production and subsequent induction of IFN‐γ‐producing T cells

Dendritic cells (DC) from diabetes‐prone NOD mice and patients with type 1 diabetes (T1D) produce excess IL‐12 that drives development of β‐cell‐destroying IFN‐γ‐producing T cells. The molecular mechanisms that control IL‐12 production in T1D are unclear. In this study, we report that β‐catenin, a multifunctional protein involved in inflammation, is dramatically increased in DC from NOD mice. We further investigated the mechanisms leading to accumulation of β‐catenin in NOD DC and its role in the inflammatory pathogenic responses associated with T1D. Hyperphosphorylation of β‐catenin at a stabilizing residue, serine 552, mediated by activation of Akt, appears to lead to β‐catenin accumulation in NOD DC. Elevated β‐catenin in DC correlated with IL‐12 production and induction of IFN‐γ‐producing CD4 cells. On the one hand, knockdown/inhibition of β‐catenin significantly reduced NOD DC production of IL‐12 and their ability to induce IFN‐γ‐producing CD4 cells. On the other hand, overexpression of β‐catenin in control DC resulted in increased IL‐12 production and induction of IFN‐γ‐production in T cells. Additionally, we found that β‐catenin inhibitors decreased NF‐κB activation in NOD DC and IFN‐γ production by NOD T cells in vivo. These data strongly suggest that accumulation of β‐catenin in DC from NOD mice drives IL‐12 production, and consequently, development of pathogenic IFN‐γ‐producing T cells. Targeting the defect responsible for β‐catenin accumulation and subsequent overproduction of pro‐inflammatory cytokines by NOD DC could be an effective therapeutic strategy for the prevention and/or treatment of T1D. Stabilizing phosphorylation of β‐catenin at Ser552 leads to its accumulation in NOD DC and subsequent inflammatory response.