IL-17-producing CD4+ T (Th17) cells have recently been defined as a separate effector T cell lineage distinct from Th1 and Th2 cells. Both Th17 and Th1 responses are elevated in animal models of colitis and in patients with inflammatory bowel disease (IBD). Although IL-12-driven excessive Th1 response against commensal bacterial antigen has been widely accepted as a major pathway in IBD pathogenesis, recent studies implicate a pivotal role for the IL-23-Th17 cell axis in experimental IBD. However, the differentiation and interaction of commensal bacterial antigen-specific Th17 and Th1 effector cells in intestine and their roles in pathogenesis of IBD remain undefined. We recently identified enteric bacterial flagellin as immunodominant antigen in experimental colitis and in patients with Crohn's disease. We have generated a TCR transgenic mouse line that is specific for CBir1 flagellin, one of such commensal bacterial flagellins. CBir1-specific Th17 and Th1 cells can be isolated from these CBir1 transgenic mice and transfer disease in immunodeficient mice. Intestinal dendritic cells likely play a critical role in the host immune response to these commensal flagellins. Multiple subsets of DC exist in lamina propria. LP DCs, but not spleen DCs, express high levels of TLR5, and, in response to flagellin stimulation, LP DCs produce high amounts of IL-6 and IL-23 which are required for Th17 development, as well as of IL-12 which drives Th1 cell development. We hypothesize that 1) Lamina propria DC and spleen DC respond differently to CBir1 flagellin stimulation. Lamina propria DCs drive T cell development into both Th1 and Th17 pathways whereas spleen DCs only promote T cell development into Th1 pathway; 2) Myeloid LPDCs preferentially induce CBir1 flagellin-specific Th17 cell development whereas another subset of LPDC drive Th1 cell pathway; 3) Activation of TLR5 signaling by CBir1 flagellin induces LPDC production of TGF2 and IL-23 which drive Th17 cell development and survival in lamina propria.
In normal hosts there is a dialogue between the microbiota, innate immune cells, including epithelial cells, and the adaptive immune cells that is able to maintain homeostasis and prevent inflammation. In IBD this dialogue is disturbed such that inflammation results. The major working hypothesis concerning the pathogenesis of IBD is that the normal intestinal microbiota is the stimulus driving the inflammatory disease and that adaptive immune CD4+ T cells are the effector cells mediating disease in genetically susceptible individuals. However, the mechanisms involved are still undefined. Many of the IBD susceptibility gene loci identified in both mouse and humans appear to involve the innate immune system. Among innate immune cells, dendritic cells (DC) are the key players in directing T cell responses to antigens, including those of commensal bacteria. Multiple subsets of DC are present in lamina propria. This project will explore how different subsets of lamina propria DC respond to recently defined dominant bacterial antigens of Crohn's disease, and how they instruct pathogenic effector T cell development in the intestine. These studies will provide an important rationale to develop a novel, commensal bacterial antigen and cytokine based therapeutic approach to improve the lives of patients with IBD. ? ? ?
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