Regulation of Mucosal Lymphocytes

描述（由申请人提供）：肠道相关淋巴组织必须在急性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”炎症以及慢性炎症性肠病（IBD）相关的特发性类型炎症之间维持繁琐的平衡。在这种失调的炎症的中心是T细胞及其活性水平，这是负责过量的细胞因子和其他介质负责炎症。因此，了解T细胞活化和下调的机制对于了解IBD和治疗操纵肠道炎症的潜力至关重要。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共刺激或共抑制的次级信号修饰。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）蛋白的背景下对抗原的特异性亲和力以及分别伴随的阳性或阴性共刺激和共抑制信号的编译来调节。大多数T细胞的主要次级共刺激和共抑制信号分别是由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。该研究计划通过产生不同的CEACAM 1同种型来研究癌胚抗原相关细胞粘附分子1（CEACAM 1）作为共抑制或共刺激分子的作用，这些同种型分别具有长或短的细胞质尾，这些尾是通过选择性剪接产生的。因此，我们提出了以下具体目标：（1）通过开发特异性敲低T细胞中CEACAM 1表达的动物模型，将表达长（L）胞质尾的CEACAM 1定义为T细胞上的共抑制分子，并从所涉及的配体和细胞内信号通路两方面定义这种抑制发生的分子机制;（2）确定表达短（S）胞质尾的CEACAM 1同种型是否共刺激TCR/CD 3复合物信号传导和肠道炎症的发展，通过产生过表达这些形式的转基因动物和表征T细胞活化期间T细胞中CEACAM 1-L和-S表达，和;（3）确定T细胞上的CEACAM 1是否可以在其他细胞类型的负调节中起作用以及它们对接触依赖性T和B细胞调节的影响。这些研究将确定CEACAM 1是否是一种新型的非CD 28相关分子，可以调节T细胞并作为炎症性疾病（如IBD）的治疗靶点。

DESCRIPTION (provided by applicant): 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.