This project focuses on how antigens are processed in the intestine of mice. While it is clear that the outcome of oral antigen exposure can be either positive, i.e., the development of mucosal IgA responses, and in some cases the induction of systemic immunity as well, or negative, i.e., the induction of oral tolerance, the details of why one or the other outcome occurs is complex and poorly understood. While it is known that the antigen formulation, the presence of adjuvants, and the antigen dose, as well as genetic factors, can affect mucosal immune responses, how these act to influence immunity has never been established. Prior studies have established the presence of different antigen-presenting cell populations in the Peyer?s patch and lamina propria of the intestine. We have described the presence of at least two populations of dendritic cells (DCs) in the Peyer?s patch, which is the primary inductive site for mucosal immune responses. One population of DCs appears to be immature and poised for capture of antigens transported from the intestinal lumen into the Peyer?s patch as it is present in a dense layer just beneath the intestinal epithelium overlying the Peyer?s patch follicle in a region referred to as the subepithelial dome (SED). A second population of more mature cells is present in the major T cell regions of the Peyer?s patch, the interfollicular regions (IFR). These findings suggest that oral antigens are taken up by immature DCs and following migration and differentiation (or activation), these cells present antigens to T cells in the IFR. Another possibility is that such antigen-loaded DCs migrate to draining mesenteric lymph nodes where they act to induce primary T cell responses. A third population of DCs appears to be of the less mature phenotype and is present in the B cell follicles of the Peyer?s patch. How these different DCs act to present intestinal antigens is the focus of this project. The studies will entail the isolation and further characterization of DCs from the Peyer?s patch, mesenteric lymph nodes, and lamina propria. This will involve studies of surface phenotype by flow cytometry, cytokine production by RT-PCR or isolated and stimulated cells, and the ability to induce T cell differentiation in vivo. Finally, the ability of mucosal adjuvants such as cholera toxin, and different immunization regimens to affect DC antigen presentation, will be explored. Findings with DCs will be compared to antigen loading and phenotypic changes in other antigen presenting cell populations, such as B cells and monocyte/macrophages from intestinal lymphoid tissue. - dendritic cell, Peyer?s patch, mucosal immunity, Th1, Th2, lymphcyte, cytokine, antigen presenting cell, immunology, chemokine
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