Insulin-dependent diabetes induced by pancreatic beta cell expression of IL-15 and IL-15R?

Abstract

Increased serum levels of IL-15 are reported in type 1 diabetes (T1D). Here we report elevated serum soluble IL-15R? levels in human T1D. To investigate the role of IL-15/IL-15R? in the pathogenesis of T1D, we generated double transgenic mice with pancreatic ?-cell expression of IL-15 and IL-15R?. The mice developed hyperglycemia, marked mononuclear cell infiltration, ?-cell destruction, and anti-insulin autoantibodies that mimic early human T1D. The diabetes in this model was reversed by inhibiting IL-15 signaling with anti-IL2/IL15R? (anti-CD122), which blocks IL-15 transpresentation. Furthermore, the diabetes could be reversed by administration of the Janus kinase 2/3 inhibitor tofacitinib, which blocks IL-15 signaling. In an alternative diabetes model, nonobese diabetic mice, IL15/IL-15R? expression was increased in islet cells in the prediabetic stage, and inhibition of IL-15 signaling with anti-CD122 at the prediabetic stage delayed diabetes development. In support of the view that these observations reflect the conditions in humans, we demonstrated pancreatic islet expression of both IL-15 and IL-15R? in human T1D. Taken together our data suggest that disordered IL-15 and IL-15R? may be involved in T1D pathogenesis and the IL-15/IL15R? system and its signaling pathway may be rational therapeutic targets for early T1D.