The butyrophilin-like (Btnl) molecules share similarities with the B7 family of costimulatory molecules for T cells, yet no functions are known. They are encoded in the major-histocompatibility complex (MHC) locus, a region of the genome known to be highly relevant in many diseases. Recently, Professor Hayday's lab identified a novel immunoglobulin-related molecule, Skint1, which appears to be a selection determinant for skin gamma delta T cells. Furthermore, in the absence of Skint1 and normal skin gamma delta T cells, mice develop spontaneous skin inflammation and are susceptible to skin carcinomas. Hence, Skint1 seems to underpin key aspects of skin immune surveillance. Interestingly, Skint1 shares close sequence homology with Btnl1, 4 and 6; moreover, whereas Skint1 is expressed specifically in thymus and skin epithelia, Btnl1, 4 and 6 are expressed specifically by intestinal epithelia. The gut is a site of chronic immune stimulation where the control of tissue inflammation and stress responses is very important. Therefore, the functional relatedness of Skint1 and the Btnl family provoked our hypothesis that Btnl1 and its relatives may be novel regulators of immunosurveillance, by interacting with intraepithelial lymphocytes (IEL) in the gut. Indeed, human Btnl2 is genetically associated with sarcoidosis and ulcerative colitis. To investigate Btnl1, I will use novel anti-Btnl1 antibodies, a Btnl1-Fc fusion protein and Btnl1 knockout mice to define situations in which Btnl1 receptor engagement occurs and the significance of this interaction. I will also attempt to identify the Btnl1 receptor on IEL. Finally, I wish to address the role of Btnl1 in immune surveillance, by examining the interaction of IEL and Btnl1+ cells in a mouse model of epithelial stress. By this, I hope to be able to place Btnl1 in the context of tumour immunology and inflammatory diseases of the gut, by characterising a potential target for clinical manipulation.
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