The intestine plays an important role in host protection and immune system modulation. To detect pathogenic organisms a large number of immune cells circulate through the gastrointestinal tract, but the mechanisms underlying the trafficking of immune cells are still poorly understood. A new class of immunoregulatory cells has been recently identified. These cells express the transcriptional regulator RORyt that regulates expression of key cytokines including IL-17 and IL-22, and is critical for differentiation of lymphoid structures in the intestine. In this application we aim to define the mechanisms regulating the development and trafficking of such cells into the intestinal mucosa. These studies are a logical development of our previous application, and build upon our recently published observations on the role of chemokines in the trafficking of cells into the intestine. In addition, we plan to examine the role of IL-23 in the development and function of RORyt+ cells. Genetic studies in humans indicate an association between increased IL-23 signaling and development of IBD. Furthermore, our own transgenic studies show that systemic expression of IL-23 subunit p19 results in severe inflammation. It remains unclear so far if disturbances in IL-23 signaling in the intestine is sufficient to promote inflammation at to what degree this response depends on RORyt+ cells. To address the role of chemokines and IL-23 in the development, trafficking and function of RORyt+ cells in the intestine we will: 1) define the role of chemokines in the distribution of RORyt+ cells in the intestine; 2) define the contribution of IL-23 to the development and function of RORyt+ cells during homeostasis and disease.
In this application we aim to define the mechanisms regulating the development, trafficking and function of a specialized group of cells in the intestine. These cells have been shown to produce cytokines that promote inflammatory bowel disease. Our studies will hopefully identify critical factors controlling the migration and activity of such cells and therefore contribute to the development of new treatments for diseases of the intestine.
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