Inflammatory bowel diseases (IBD) are diseases of immune dysregulation. Evidence from a number of mouse models of IBD, and emerging data from human studies, support a central role for dysregulated CD4 T cell responses to components of the enteric flora as a common pathogenetic mechanism. Effector T cell responses linked to IBD have traditionally been viewed in the context of the Th1/Th2 paradigm, wherein recognition of enteric bacterial antigens elicit either prototypical Th1 cytokines (IFN-gamma and TNF-alpha) or Th2 cytokines {IL-4, IL-13, and IL-5). In many mouse models of IBD, and in Crohn's disease, the prevailing view is that it is a dysregulated Th1 response that is pathogenic. However, recent studies point to a need for critical reassessment of the existing Th1 paradigm. In experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis, both conventionally viewed as Th1 disease models, it was found that effector T cell production of IL-17, and not IFNgamma, was linked to disease pathogenesis, challenging the significance of classical Th1 cells in the induction and maintenance of chronic inflammatory disease. These effector cytokines were reciprocally induced by distinct IL-12 family members, such that IL-12 favored development of IFNgamma-producing T cells, whereas IL-23 favored IL-17 producers. Notably, expression of IFNgamma or IL-17 tended to be mutually exclusive in individual T cells. These studies have raised important questions regarding the lineage relationships between IL-17- versus IFNgamma-producing """"""""Th1"""""""" cells, and the respective roles of these cytokines in disease pathogenesis or protection. We hypothesize that existing Th1 models of IBD, and Crohn's disease, are in fact due to dysregulated IL-17 responses to the intestinal flora, and that IFNgamma-producing T cells are non-pathogenic effectors from which IL-17-producing, pathogenic effectors can develop under the appropriate conditions. To test our hypothesis, we have generated a novel IFNgamma reporter transgenic model and will generate a complementary IL-17 reporter model to examine the induction, lineage relationships and regulation of these T cell phenotypes in the context of an antigen-specific mouse model of IBD. Further, we will explore the interplay of regulatory T cells with these distinct effector T cell populations, utilizing an IL-10 reporter model that we have developed for independent studies of intestinal regulatory T cell biology. Ultimately, these studies will form the basis for comparative studies with T effector and T regulatory cells isolated from normal and diseased human intestinal tissues, about which little is known.
Our specific aims are to test three distinct, but related, aspects of the above hypothesis: 1. The IL-23/IL-17 cytokine axis is required for immunopathogenesis in IBD: 2. IL-17- producing CD4 T cells represent a distinct population of Th1 effector cells that develop from IFNgamma-producing intermediates at tissue effector sites, such as the intestinal lamina propria: and. 3. IL-10-producing regulatory T cells suppress the development and maintenance of IL-17-producing effector T cells in the intestinal lamina propria.
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