The gut-associated lymphoid tissue must manage a tedious balance between """"""""physiologic"""""""" and """"""""tissue destructive"""""""" inflammation associated acutely with exposure to pathogens and other exogenous assaults and chronically in the setting of the idiopathic types of inflammation associated with inflammatory bowel disease (IBD). At the center of this dysregulated inflammation is the T cell and its activity levels, which are responsible for the excess quantities of cytokines and other mediators responsible for the inflammation. Understanding the mechanisms of T cell activation and downregulation are thus critical to gaining an understanding of IBD and the potential to therapeutically manipulate intestinal inflammation. T cells are primarily activated by signals delivered to the antigen-specific receptor, the T cell receptor (TCR)/CD3 complex, which is modified by secondary signals that are either co-stimulatory or co-inhibitory. The responsiveness of T cells are tunable through the specific affinities of its TCR/CD3 complex to antigen in the context of major histocompatibility complex (MHC) proteins and the compilation of the concomitant positive or negative co-stimulatory and co-inhibitory signals, respectively. The major secondary co-stimulatory and co-inhibitory signals for the majority of T cells are those delivered by either CD28 or CTLA-4, respectively. It has, however, been increasingly evident that many T cells, including those in the intestine, do not express these molecules and, as a corollary, other molecules may provide such functions. This grant proposes to investigate the role of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) as a co-inhibitory or co-stimulatory molecule through the generation of distinct CEACAM1 isoforms that possess a long or short cytoplasmic tail, respectively, which are generated by alternate splicing. We, therefore, propose the following specific aims: (1) Define CEACAM1 expressing a long (L) cytoplasmic tail as a co-inhibitory molecule on T cells by the development of an animal model that knocks-down CEACAM1 expression specifically in T cells and define the molecular mechanisms by which this inhibition occurs both in terms of the ligand involved and the intracellular signaling pathways; (2) determine whether CEACAM1 isoforms expressing a short (S) cytoplasmic tail are co-stimulatory of TCR/CD3 complex signaling and the development of intestinal inflammation through the generation of transgenic animals that over-express these forms and the characterization of CEACAM1-L and -S expression in T cells during T cell activation, and; (3) determine whether CEACAM1 on T cells can function in the negative regulation of other cell types and their implications for contact-dependent T and B cell regulation. These studies will determine whether CEACAM1 is a novel non-CD28-related molecule that can regulate T cells and act as a therapeutic target for inflammatory conditions such as IBD. ? ? ?
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