Project Summary Type I diabetes (T1D) is a chronic autoimmune disease in which T cells destroy insulin-producing pancreatic β cells. T1D results from a complex interaction between genetic predisposition and environmental factors. Completely defining the genetic and environmental factors that contribute to disease susceptibility is crucial to finding successful therapies in the treatment and prevention of T1D. Human IL27 (encodes a subunit of the cytokine interleukin (IL)-27) is a T1D candidate gene located in a susceptibility region on chromosome 16. The function of IL-27 in T1D pathogenesis is unknown. The long-term goal of this project is to define the role of IL-27 in the progression of T1D. CD8 T cells are the main effectors mediating β cell damage but they require help from CD4 T cells. Previous studies with both human and mouse have shown that IL-27 signaling can regulate T cell function. Our lab has generated non-obese diabetic (NOD) mice deficient in IL-27 or IL-27 receptor (IL-27Ra) and demonstrated that IL-27 signaling in both CD4 and CD8 T cells is important for diabetes development. Additionally, our preliminary data show that lack of direct IL-27 signaling results in decreased CD8 T cell frequency, proliferation, and cytokine production in the pancreatic islets. Together these observations lead us to hypothesize that IL-27 signaling is important for the accumulation and sustained effector function of autoreactive CD8 T cells. In Aim 1, we will determine the mechanism by which IL-27 signaling directly promotes the accumulation and sustained effector function of autoreactive CD8 T cells. These experiments will test the intrinsic effect of IL-27 signaling on CD8 T cell homing and differentiation into pathogenic effectors. In Aim 2, we will determine the mechanism by which direct IL-27 signaling promotes the ability of CD4 T cells to help autoreactive CD8 T cells. Pathogenic CD8 T cells require help from CD4 T cells for activation and propagation. Therefore, these experiments will test the effect of CD4 T cell- intrinsic IL-27 signaling on the differentiation of CD8 T cells in the pancreatic islets. This proposal will advance our understanding of the differentiation and effector function of autoreactive CD8 T cells during the progression of T1D. This is in line with the mission of NIDDK, as the results of this project could lead to identification of the IL-27 signaling pathway as a novel therapeutic target for the treatment or prevention of T1D.