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Development of type 1 diabetes in the nonobese diabetic (NOD) mouse is preceded by an immune cell infiltrate in the pancreatic islets. The exact role of the attracted cells is still poorly understood. Chemokine CCL2/MCP-1 is known to attract CCR2+ monocytes and dendritic cells (DCs). We have previously shown that transgenic expression of CCL2 in pancreatic islets via the rat insulin promoter induces nondestructive insulitis on a nonautoimmune background. We report here an unexpected reduction of diabetes development on the NOD background despite an increased islet cell infiltrate with markedly increased numbers of CD11c+ CD11b+ DCs. These DCs exhibited a hypoactive phenotype with low CD40, MHC II, CD80/CD86 expression, and reduced TNF-α but elevated IL-10 secretions. They failed to induce proliferation of diabetogenic CD4+ T cells in vitro. Pancreatic lymph node CD4+ T cells were down-regulated ex vivo and expressed the anergy markerGrail . By using an in vivo transfer system, we show that CD11c+ CD11b+ DCs from rat insulin promoter-CCL2 transgenic NOD mice were the most potent cells suppressing diabetes development. These findings support an unexpected beneficial role for CCL2 in type 1 diabetes with implications for current strategies interfering with the CCL2/CCR2 axis in humans, and for dendritic cell biology in autoimmunity.

Pancreatic islet expression of chemokine CCL2 suppresses autoimmune diabetes via tolerogenic CD11c + CD11b + dendritic cells

Pancreatic islet expression of chemokine CCL2 suppresses autoimmune diabetes via tolerogenic CD11c ⁺ CD11b ⁺ dendritic cells