Epithelial TLR signaling and IgA production

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DESCRIPTION (provided by applicant): Several studies suggest that normal intestinal epithelial cells (IECs) express Toll like receptors and that signaling through these receptors may play a role in maintaining intestinal homeostasis. To test the role of epithelial TLR signaling in mucosal immune responses, we generated transgenic mice that express a constitutively active form of TLR4 in the intestinal epithelium (V-TLR4 mice). Expression of this transgene by IEC mimicked signaling by Toll ligands and promoted the expression of a select group of chemokines and the TNF family member APRIL. These combined activities resulted in increased recruitment of B cells to the lamina propria and increased secretion of IgA into the intestinal lumen. The observation that increased TLR signaling in the intestinal epithelium induces increased secretion of IgA in the intestinal lumen indicates the existence of a epithelium-based mechanism to respond to bacterial or viral challenges with an appropriate increase in the level of IgA. In this application we aim to understand the basic components of this mechanism and inquire if increased TLR signaling in the epithelium enhances or suppresses the immune response. Knowledge derived from these studies is likely to contribute to a better understanding of the role of TLR signaling in epithelial function and to the development of better vaccination approaches. Specifically we will 1) define the mechanisms whereby constitutive TLR signaling in the gut epithelium promotes increased production of chemokines and IgA and, 2) determine if constitutive TLR signaling in the gut epithelium affects active immunization and tolerance. Cells lining the intestine express surface receptors that may inform the body about the presence of infectious agents. To test the role of such receptors in mucosal immune responses, we generated strains of mice that have a large number of these receptors. We found that these animals secrete large amounts of antibodies in the intestine. As antibody production is a key component of the immune defense, we conclude that these receptors play a key role in the immune response to infection. The work presented in this application aims to understand how the signals elicited from these receptors promote antibody production and whether these "engineered" animals have stronger immune systems. Insights from these studies may contribute to development of better vaccines.