Role Of The Thymus Leukemia Antigen In Mucosal Immunity

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DESCRIPTION (provided by applicant): The gut mucosa represents a major entry point for many pathogens and is the target of a variety of inflammatory conditions, including the idiopathic inflammatory bowel diseases (IBD) ulcerative colitis and Crohn's disease. Emerging evidence suggests a critical role of CD8-expressing intraepithelial lymphocytes (IEL) in regulating immune responses in the intestine. Recent studies have indicated that CD8 interacts at high affinity with the thymus leukemia (TL) antigen, a nonclassical MHC class I molecule that is constitutively expressed on intestinal epithelial cells. Structural studies have demonstrated that the putative antigen-presenting groove of TL is occluded, indicating that the interaction between TL and CD8 occurs independent of TL-associated peptides. While a number of functions for TL have been proposed, its immunological role in the gut mucosa remains enigmatic. In this R21 proposal we will test the hypothesis that TL controls IEL functions and the development of IBD. To establish the in vivo role of TL in mucosal immunity we have generated a novel mouse strain that is selectively deficient in TL expression. Using these animals, we propose two integrated specific aims to investigate the role of TL in IEL function and IBD development: Aim 1 will investigate the contribution of TL expression in intestinal T cell function and Aim 2 will investigate the role of TL expression in the development of IBD, using a spontaneous model and an induced model. The long- term goal of this project is to determine the molecular mechanisms involved in TL-controlled mucosal immune responses. PUBLIC HEALTH RELEVENCE: Results from the proposed studies should prove useful for developing improved vaccines and therapeutic strategies against intestinal infections. In addition, the proposed studies will be helpful for the development of new therapies for inflammatory conditions of the gastrointestinal tract (e.g., ulcerative colitis and Crohn's disease).