Type 1 diabetes (T1D) is currently an incurable disease because the autoimmune response that destroys insulin-producing b islet cells cannot be controlled. Autoreactive CD4 cells are key orchestrators of T1D. Their escalating responses ultimately escape regulation, leading to acute inflammation in the pancreas and diabetes onset. While it is clear that IFN-g producing Th1 cells are essential to disease pathogenesis, whether or when IL-17-producing Th17 cells contribute to T1D is unknown. Th17 cells that secrete IL-17A and to a lesser extent IL-17F have been implicated in several autoimmune diseases. Our studies show that IL-17A- and IFN-g- secreting CD4 T cells are distinct subsets in pancreatic infiltrates during the insulitis phase and at T1D onset in NOD mice, whereas IL-17F is not detected. In addition, elevated serum levels of IL-17A and IFN-g herald the onset of hyperglycemia. We now find that IL-17A+ CD4 T cells greatly accelerate diabetes in normal (WT) NOD mice. On the basis of our findings and the detection of IL-17A+ cells in T1D patients, we hypothesize that Th17 cells are important contributors to the pathogenesis of T1D. However, without additional tools, it will not be possible to directly address mechanisms that regulate the responses of these cells or their effector functions that could be targeted to control the autoimmune response. Our goal is to develop a novel IL-17A reporter mouse on the NOD background that will enable analysis of the development and responses of Th17 cells in situ by lineage tracing during progression to T1D and, in a future R01 grant we plan to pursue studies of the regulation of Th17 cells in T1D. We propose to use bacterial artificial chromosome (BAC)-based gene reporter and gene knockin strategies to create mice that will enable identification and isolation of CD4 cells that acquire Il17a gene expression, as reported by expression of a GFP-Cre fusion protein inserted in the Il17a locus. We will use a double reporter strategy by breeding these animals to Rosa26-YFP NOD mice to indelibly mark cells with a history of IL-17A production. These mice will provide a novel tool to unequivocally study the contributions of Th17 cells to T1D and the potential functional interrelationships between Th1 and Th17 cells that lead to diabetes onset. The ability to identify changes in the development of Th17 cells and their functions will facilitate the design of appropriate strategies to control autoaggressive CD4 cells and provide new insights into the biology of Th17 cells.
It will be crucial to control the autoimmune response to cure T1D;however, tools to identify changes that occur in the CD4 T cells that orchestrate the disease are lacking. We propose to generate a novel reporter mouse using the NOD mouse model of T1D that will permit tracking of a subset known as Th17 cells, whose functions are controversial but implicated in other diseases. This essential tool will greatly improve our understanding of T1D and the potential for targeting the CD4 cell population.