Co-expression of IL-15 and IL-15Rα on pancreatic β islet cells induced insulin dependent diabetes mellitus in mice (161.2)

Abstract Interleukin-15 (IL-15) is a pro-inflammatory cytokine that stimulates T and natural killer (NK) cells. Increased serum levels of IL-15 are found in type 1 diabetes (T1D). Here we showed increased serum levels of soluble IL-15Rα in T1D. Moreover, co-expression of IL-15 and IL-15Rα on pancreatic beta islet cells induced insulin dependent diabetes mellitus in mice. Inhibiting IL-15 signaling by blocking IL-15 trans-presentation with TMβ1 (anti-CD122) or by Jak3 inhibitor Tasocitinib completely reversed diabetes in the mice. Islets purified from the double transgenic mice demonstrated increased expression of pro-inflammatory cytokines/chemokines and increased surface expression of MHC class I/II and ICAM-1. Depletion of CD4 cell at the diabetes onset reversed hyperglycemia while CD8 and NK cell depletion had no effect. Furthermore, CD4 cells purified from the double transgenic mice proliferated in response to wild type islets in vitro. Moreover, in non-obese diabetic (NOD) mice, inhibiting IL-15 signaling delayed diabetes development at pre-diabetic stage. Taken together, our data suggested that disordered IL-15 and IL-15Rα may be involved in the pathogenesis of type 1 diabetes and IL-15/IL15Rα pathway may be a rational therapeutic target for type 1 diabetes.