Regulation of Mucosal Lymphocytes

肠道相关淋巴组织必须在急性与暴露于病原体和其他外源性攻击相关的“生理性”和“组织破坏性”炎症以及慢性与炎性肠病相关的特发性类型炎症之间维持繁琐的平衡。 理解并因此能够干预这些类型的炎症的核心是需要更深入地了解T细胞由肠道中的专业和非专业抗原呈递细胞调节的机制。 许多免疫介导的肠道疾病直接依赖于Y细胞及其细胞因子产物的活化。 因此，理解管理T细胞的功能水平的分子机制与肠道相关疾病的发病机制越来越相关。 T细胞主要由递送至抗原特异性受体（T细胞受体（TCR）/CD 3复合物）的信号激活，所述抗原特异性受体由刺激性或抑制性的次级信号修饰。 因此，T细胞的反应性可通过其TCR/CD 3复合物在主要组织相容性复合物（MHC）分子的背景下对抗原的特异性亲和力以及伴随的阳性和阴性次级信号的编译来调节。 大多数T细胞的主要次级刺激和抑制信号分别是由CD 28或CTLA-4递送的信号。 然而，越来越明显的是，许多T细胞，包括肠道中的T细胞，不表达这些分子，并且作为推论，其他分子可能提供这些功能。该授权申请提出研究CEACAM 1功能负调节由抗原/MHC介导的信号启动的粘膜T细胞活性的新假设。 因此，我们提出了以下具体目标：（1）检测人和小鼠粘膜T细胞中CEACAM 1的表达和功能，包括确定CEACAM 1是否调节T辅助细胞1（Th 1）和Th 2细胞因子的产生;（2）通过测试野生型CEACAM 1-Fc融合蛋白，而不是嗜同性结合位点突变的融合蛋白，在体外抑制粘膜T细胞功能;（3）确定CEACAM 1胞质尾区的磷酸化状态是否调节CEACAM 1的细胞分布和抑制功能;（4）确定CEACAM 1特异性抗体和CEACAM 1-Fc融合蛋白，而不是嗜同性结合位点突变的CEACAM 1-Fc融合蛋白，可以抑制体内Th 1介导的炎症。

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.