Antigen Recognition at Intestinal Epithelial Interphases

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DESCRIPTION (provided by applicant): The intestinal immune system coexist in intimate association with the intestinal microbiota and the outcome of this interaction is determined by the functional properties of (dendritic cells) DC, which have a key role for immune responses by enabling antigen sampling, pathogen recognition and innate host defenses. The importance of this interaction is underscored by mounting evidence that dysregulation of antigen recognition and processing of the intestinal microbiota may be a common disease mechanism in Inflammatory Bowel Diseases (IBD). The proposed studies are directed to determine the role of DC subsets, which are responsible in mediating these critical host defense functions in the context of normal and inflamed intestinal mucosa. We demonstrate that the intestinal mucosa contains an extensive myeloid derived DC system, which is not restricted to Payer's patches (PP) but populates the entire lamina propria of the small and large intestine. This system is comprised of distinct DC subsets distinguished by the expression of the fractalkine (CX3CL1) receptor, CX3CR1. These DC represent a novel pathway for antigen recognition in the intestine, through their ability to extent processes into the intestinal lumen for the direct sampling of the intestinal microbiota. Our studies thus far show functional significance of CX3CR1 in the regulation of luminal antigen sampling, pathogen uptake and host defense by intestinal DC. This project will test the overall hypothesis that CX3CR1 expression regulates a myeloid derived DC system, which constitutively populates the lamina propria facilitating constant monitoring of the intestinal microbiota and serving as a 'first line' of mucosal defense. This hypothesis will be tested through studies aimed to determine in aggregate the mechanisms by which CX3CR1 regulates the development and function of DC subsets in the mucosal immune system. The coordinated and complementary strategies of the specific aims of this proposal will provide insights into the responses of intestinal DC required to balance the regulation of self-reactive and pathogen specific adaptive immune responses with an immediate protective defense against microbial infections.