Regulation of Mucosal Lymphocytes

Brigham And Women'S Hospital, Boston MA

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Abstract

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. Central to understanding and thus being to be able to intervene into these types of inflammations is the need to gain a deeper understanding into the mechanisms by which T cells are regulated by professional and nonprofessional antigen presenting cells in the gut. Many immune-mediated diseases of the intestine are directly dependent upon the activation of Y cells and their cytokine products. As such, understanding the molecular mechanisms by which the functional levels of T cells are managed is increasingly relevant to the pathogenesis of gut- associated diseases. 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 stimulatory or inhibitory. The responsiveness of a T cell is thus tunable through specific affinities of its TCR/CD3 complex for antigen in the context of a major histocompatibility complex (MHC) molecule and the compilation of concomitant positive and negative secondary signals. The major secondary stimulatory and inhibitory signals for the majority of T cells are those delivered by either CD28 or CTLA-4, respectively. It has, however, become 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 application proposes to investigate the novel hypothesis that CEACAM1 functions to negatively regulate the activities of mucosal T cells initiated by antigen/MHC mediated signals. We, therefore, propose the following specific aims: (1) to examine the expression and function of CEACAM1 by human and mouse mucosal T cells including a determination of whether CEACAM1 regulates T helper 1 (Th1) and Th2 cytokine production; (2) to determine whether homophilic-CEACAM1 interactions are involved in regulating mucosal T cell functions by testing whether wild-type CEACAM1-Fc fusion proteins, but not fusion proteins mutant in the homophilic binding sites, inhibit mucosal T cell function in vitro; (3) determining whether the phosphorylation state of the CEACAM1 cytoplasmic tail regulates the cellular distribution and inhibitory functions of CEACAM1, and; (4) to determine whether CEACAM1 specific antibodies and CEACAM1-Fc fusion proteins, but not CEACAM1-Fc fusion proteins mutated in the homophilic binding site, can inhibit Th1-mediated inflammation in vivo.