Thursday, November 21, 2024
11/21/2024
PROJECT SUMMARY/ABSTRACT The immune system at mucosal sites has evolved to mediate rapid immunity to invading pathogens, while limiting over-reactive responses that drive chronic inflammation. Mechanisms of lymphocyte trafficking are essential for the function and systemic integration of the immune system, and in particular for targeting immune responses to specific mucosal and epithelial organs and tissues in the body. Despite identification of trafficking receptors for the small intestines, colon, and skin, we have limited knowledge of mechanisms of lymphocyte recruitment to the lung and to most non-intestinal mucosal sites. Defining mechanisms controlling organotypic lymphocyte homing to these tissues which will be critical for developing therapies to control immune pathologies. We have identified a novel lymphocyte chemoattractant receptor and its chemoattractant ligand, selectively expressed in lung, airways, upper GI tract, genitourinary mucosae and mucosa-associated glands including the pancreas and salivary glands. Under Aim 1 we will mechanistically probe the receptor-ligand interactions focusing on the specificity and signaling pathways activated by the novel receptor and its role as a lymphocyte vs myeloid cell chemotactic receptor. Structure-function studies will identify ligand domains for receptor binding and activation. Aim 2 will define the regulation of the receptor in the mouse, and its role in lymphocyte population of and homing to non-lymphoid tissues during homeostasis and in the setting of chronic multi-organ autoimmune inflammation. The roles of the pathway in immune cell development will be probed in mixed bone marrow chimeras in which receptor-deficient vs wild type stem cells compete for reconstitution of immune compartments in lymphoid and non-lymphoid tissues. Aim 3 will elucidate the tissue- and cell subset- specific expression of the receptor and ligand in humans. Regulation of the receptor will be studied in organotypic lymphocyte development and activation, in homeostasis, and in pulmonary immune challenge and infection. We will employ innovative approaches and develop new tools to address the fundamental role of the novel pathway in the immune system, and where possible, translate our findings from mice into humans. Results from these studies will significantly advance our understanding of the systemic organization and integration of the mucosal immune system. The mechanisms identified will provide the basis for new approaches to manipulating immunity and inflammation in the lungs and extraintestinal mucosae.
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