TCR USAGE AND FUNCTION IN IBD

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DESCRIPTION (taken from application) T-cells are likely to play a crucial role in inflammatory bowel disease (IBD) pathogenesis. Our focus has centered on the analysis of the T-cell receptor (TCR), the specific antigen recognition element of the T-cell, as a means to implicate T-cell responses to specific antigen(s) in disease pathogenesis and to potentially identify disease relevant T-cell clones. Our previous studies on TCR usage have clearly shown that a highly specific T-cell response is present in individuals with IBD and this response is characterized by persistent T-cell expansions which are shared by genetically related individuals. This directly implicates a response by T-cells in IBD affected individuals to conventional antigen(s). The major goals of this grant proposal are to further define the nature of these T-cell expansions in IBD and investigate for potential T-cell recognized antigen(s) relevant to IBD pathogenesis. Specifically, we plan to characterize: (1) the TCR usage of the IL-2 receptor positive subset of intestinal T-cells; (2) the TCR usage of the bile-duct associated T-cells in the clinically distinct subset of individuals with primary sclerosing cholangitis, and; (3) the relationship between major histocompatibility complex (MHC) and TCR usage in families with IBD. By utilizing this information on TCR usage, specific T-cell clones of interest, which express TCRs that are a part of a public or private motif, will be isolated and utilized in long-term, molecular and cellular based strategies. These strategies, which are based on rapidly emerging technologies, will aim to define the cognate antigen(s) of these potentially disease relevant T-cells, and thus allow further insight into the etiopathogenesis of IBD.