IL-17F and IL-17RC regulate the pathogenesis of type 1 diabetes in NOD mice

The role of type 17 immune responses in the pathogenesis of type 1 diabetes (T1D) has been tested in multiple studies however the importance of these pathways remains enigmatic. The function of the prototypic IL-17 family cytokine, IL-17A, has been tested most extensively and while blockade of IL-17A in NOD mice protects from the development of T1D, IL-17A deficient NOD mice have normal disease incidence. To further elucidate the role of IL-17 pathways in T1D we have tested the functions of the cytokine IL-17F and IL-17RC, a receptor for IL-17A and IL-17F, in islets and NOD mice.

We show that NOD islet infiltrates contain a population of IL-17F/IL-17A coexpressing T cells and that mouse beta cells express the IL-17RC/IL-17RA receptor complex required for IL-17F responsiveness. Stimulation of mouse islets with IL-17F, in combination with TNFa and IFNg, potently increased the expression of inflammatory markers, including chemokines and Nos2, and induced apoptotic cell death. IL-17F also suppressed the expression of beta cell signature transcripts including Pdx1, Insulin1 and Glut2, consistent with a loss of beta cell function. To determine how the combined effects of IL-17F and IL-17A regulate the development of T1D we generated IL-17RC deficient NOD mice. Islets from IL-17RC deficient mice failed to respond to both IL-17F and IL-17A. Importantly IL-17RC deficient NOD mice exhibited perturbations in the islet autoimmune response with reduced insulin autoantibody production and were protected from development of T1D. Together these data demonstrate that IL-17F has pathogenic activities in mouse islets and that the combined actions of IL-17F and IL-17A regulate the development of T1D in NOD mice.