Interleukin-15 (IL-15) is a pro-inflammatory cytokine that promotes the activation and maintenance of natural killer (NK) and CD8 (+) T-effector memory (T-EM) cells. In patients with type 1 diabetes, elevated serum levels of IL-15 have been reported. Using an assay developed in the lab, we demonstrated that the serum sIL-15Rα levels were significantly higher in patients with T1D compared with those of normal controls. To investigate whether islet overexpression of IL-15 and IL-15Rα could play a role in the pathogenesis of T1D, we generated double transgenic mice with β cell specific expression of both IL-15 and IL-15Rα under a rat insulin promoter. The mice developed hyperglycemia, marked mononuclear cell infiltration, β cell destruction and anti-insulin autoantibodies that mimic the early events of human T1D. Inhibiting IL-15 signaling with anti-IL2/IL15Rβ (anti-CD122), which blocks IL-15 transpresentation, or with the Janus kinase 2/3 inhibitor tofacitinib, reversed the diabetes in the transgenic mice. This suggested a causative role of IL-15 and IL-15Ra in the induction of insulin dependent diabetes in mice.

To further investigate whether IL-15 and IL-15Ra play a role in the pathogenesis of human type 1 diabetes, we investigated the expression of IL-15 and IL-15Ra in the islets of patients with type 1 diabetes, anti-insulin autoantibodies and normal donors. Immunohistochemistry demonstrated IL-15 expression in the islets in all T1D patients examined whereas IL-15 was detected only in the pancreatic islets in one out of four normal donors and two out of five autoantibody positive donors. Interestingly, in two cases where IL-15 was positive, we also detected islet expression of MxA, a GTPase induced by type 1 IFN (α/β) that has been reported to interfere with virus multiplication and spread. Furthermore, IL-15 and IL-15Rα mRNA levels were also higher in the islets from T1D patients compared to that from autoantibody positive donors or normal donors. The islets were microdissected based on insulin positivity using laser capture microscopy (LCM). Taken together, our data suggest that disordered IL-15 and IL-15Rα may be involved in the pathogenesis of human T1D.