Regulating tolerogenic signals by inhibitory co-receptors

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Immunoreceptors play an important role in balancing the threshold of cellular activation is critical in the immune response to tumours, pathogens or allergens, to arrest autoimmune and infectious disease and to provoke immunological memory to vaccination. We have discovered that Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1-CD31) is a new immunoreceptor, that belongs to a very important family of proteins, the Ig-ITIM superfamily which is a subset of the immunoglobulin superfamily. We wish to determine if PECAM-1 functions as an inhibitory receptor in the lymphoid microenvironment using genetically engineered mice which lack the protein. As some of the functional features may display modest features, we plan to cross the PECAM-1 deficient mice with hen egg lysozyme transgenic mice to test the importance of PECAM-1 in peripheral tolerance. We will also define its importance in T cell function. We will test if the PECAM-1 deficient mice are more susceptible to the onset of inducible autoimmunde diseases including mouse models of collagen-induced arthritis and diabetes. Finally, we will produce transgenic mice expressing normal and disabled signaling motifs of PECAM-1 to test their requirement in autoimmunity.