Restoration of Immune Tolerance in Type 1 Diabetes by Modulating Interleukin-2 Receptor Signaling

Abstract

Abstract Type 1 diabetes (T1D) is an organ-specific autoimmune disease, characterized by the destruction of insulin-producing beta cells in pancreatic islets. A variety of lymphocytes, including T cells and natural killer (NK) cells infiltrate into the islets. Their roles in T1D are rather different--effector T cells and NK cells accelerate, while regulatory T cells, dampen the development of T1D. Signaling through interleukin-2 (IL-2) receptor beta (IL-2Rβ, also known as CD122) is critical for the differentiation and function of both T cells and NK cells. However, it remains poorly understood how these cells respond to IL-2Rβ signaling during the development of T1D. Here we show that in non-obese diabetic (NOD) mice, the most commonly used animal model for human T1D, administration of a non-immunogenic monoclonal antibody (mAb) selectively ablates pathogenic cells, including memory CD4+ T cells, CD8+ T cells and NK cells. In contrast, CD4+ Foxp3+ regulatory T (Treg) cells are only mildly affected. This leads to significantly elevated ratios between Treg cells and pathogenic cells. This reset balance preferentially occurs in pancreatic islets, without systemic immunosuppression. Importantly, IL-2Rβ blockade suppresses both insulitis and diabetes in NOD mice. Moreover, IL-2Rβ blockade significantly suppresses interferon gamma (IFN-γ) production in T cells and NK cells, but promotes interleukin-17 (IL-17) production in CD4+ T cells. Therefore, the modulation of IL-2Rβ signaling represents a novel and efficient approach to restore immune tolerance in T1D.