IL-21 is required for the development of type 1 diabetes in NOD mice
Tom Van Belle, Andrew P. R. Sutherland, Andrea L. Wurster, Akira Suto, Monia Michaud, Dorothy Zhang, Michael J. Grusby, Matthias von Herrath
IL-21 is a type 1 cytokine that has been implicated in the pathogenesis of type 1 diabetes (T1D) via the unique biology of the Non-Obese Diabetic (NOD) mouse strain. The aim of this study was to investigate a causal role for IL-21 in T1D. We generated IL-21R deficient NOD mice and C57Bl/6 mice expressing IL-21 in pancreatic β-cells, allowing the determination of the role of insufficient and excessive IL-21 signaling in T1D. Deficiency in IL-21R expression renders NOD mice resistant to insulitis, production of insulin autoantibodies and onset of T1D. The lymphoid compartment in IL-21R-/- NOD is normal, does not contain an increased regulatory T cell fraction or diminished effector cytokine responses. However, we observed a clear defect in autoreactive effector T cells in IL-21R-/- NOD by transfer experiments. Conversely, over-expression of IL-21 in pancreatic β-cells induced inflammatory cytokine and chemokines, including IL-17A, IL17F, IFN-γ, MCP-1, MCP-2, IP-10, in the pancreas. The ensuing leukocytic infiltration in the islets resulted in destruction of β-cells and spontaneous T1D in the normally diabetes-resistant C57Bl/6 and NOD x C57Bl/6 backgrounds. This work provides demonstration of the essential pro-diabetogenic activities of IL-21 on diverse genetic backgrounds (NOD and C57BL/6) and indicates that IL-21 blockade could be a promising strategy for interventions in human T1D.