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BackgroundIn Type 1 diabetes, the insulin-producing β-cells within the pancreatic islets of Langerhans are destroyed. We showed previously that immunotherapy with Bacillus Calmette-Guerin (BCG) or complete Freund’s adjuvant (CFA) of non-obese diabetic (NOD) mice can prevent disease process and pancreatic β-cell loss. This was associated with increased islet Regenerating (Reg) genes expression, and elevated IL-22-producing Th17 T-cells in the pancreas.ResultsWe hypothesized that IL-22 was responsible for the increased Reg gene expression in the pancreas. We therefore quantified the Reg1, Reg2, and Reg3δ (INGAP) mRNA expression in isolated pre-diabetic NOD islets treated with IL-22. We measured IL-22, and IL-22 receptor(R)-α mRNA expression in the pancreas and spleen of pre-diabetic and diabetic NOD mice. Our results showed: 1) Reg1 and Reg2 mRNA abundance to be significantly increased in IL-22-treated islets in vitro; 2) IL-22 mRNA expression in the pre-diabetic mouse pancreas increased with time following CFA treatment; 3) a reduced expression of IL-22Rα following CFA treatment; 4) a down-regulation in Reg1 and Reg2 mRNA expression in the pancreas of pre-diabetic mice injected with an IL-22 neutralizing antibody; and 5) an increased islet β-cell DNA synthesis in vitro in the presence of IL-22.ConclusionsWe conclude that IL-22 may contribute to the regeneration of β-cells by up-regulating Regenerating Reg1 and Reg2 genes in the islets.

1 S. M. B. and E. N. contributed equally to this work. SummaryT helper type 17 (Th17) cells have been shown to be pathogenic in autoimmune diseases; however, their role in type 1 diabetes (T1D) remains inconclusive. We have found that Th17 differentiation of CD4 1 T cells from BDC2Á5 T cell receptor transgenic non-obese diabetic (NOD) mice can be driven by interleukin (IL)-23 1 IL-6 to produce large amounts of IL-22, and these cells induce T1D in young NOD mice upon adoptive transfer. Conversely, polarizing these cells with transforming growth factor (TGF)-b 1 IL-6 led to non-diabetogenic regulatory Th17 (T reg 17) cells that express high levels of aryl hydrocarbon receptor (AhR) and IL-10 but produced much reduced levels of IL-22. The diabetogenic potential of these Th17 subsets was assessed by adoptive transfer studies in young NOD mice and not NOD.severe combined immunodeficient (SCID) mice to prevent possible transdifferentiation of these cells in vivo. Based upon our results, we suggest that both pathogenic Th17 cells and non-pathogenic regulatory T reg 17 cells can be generated from CD4 1 T cells under appropriate polarization conditions. This may explain the contradictory role of Th17 cells in T1D. The IL-17 producing T reg 17 cells offer a novel regulatory T cell population for the modulation of autoimmunity.

SummaryWe have shown that pathogenic T helper type 17 (Th17) cells differentiated from naive CD41 T cells of BDC2Á5 T cell receptor transgenic non-obese diabetic (NOD) mice by interleukin (IL)-23 plus IL-6 produce IL-17, IL-22 and induce type 1 diabetes (T1D). Neutralizing interferon (IFN)-g during the polarization process leads to a significant increase in IL-22 production by these Th17 cells. We also isolated IL-22-producing Th17 cells from the pancreas of wild-type diabetic NOD mice. IL-27 also blocked IL-22 production from diabetogenic Th17 cells. To determine the functional role of IL-22 produced by pathogenic Th17 cells in T1D we neutralized IL-22 in vivo by using anti-IL-22 monoclonal antibody. We found that blocking IL-22 did not alter significantly adoptive transfer of disease by pathogenic Th17 cells. Therefore, IL-22 is not required for T1D pathogenesis. The IL-22Ra receptor for IL-22 however, increased in the pancreas of NOD mice during disease progression and based upon our and other studies we suggest that IL-22 may have a regenerative and protective role in the pancreatic islets.