Regulation of Mucosal Lymphocytes

描述(由申请人提供)：肠道相关淋巴组织必须在“生理性”和“组织破坏性”炎症之间达到繁琐的平衡，这种炎症与病原体和其他外源性攻击的急性相关，以及与炎症性肠病(IBD)相关的特发性炎症类型的慢性相关。这种失调炎症的中心是T细胞及其活动水平，这是导致炎症的细胞因子和其他介质过量的原因。因此，了解T细胞激活和下调的机制对于了解IBD和治疗操作肠道炎症的可能性至关重要。T细胞主要由传递给抗原特异性受体T细胞受体(TCR)/CD3复合体的信号激活，该复合体被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/CD3复合体对主要组织相容性复合体(MHC)蛋白中抗原的特异性亲和力以及相应的阳性或阴性共刺激和共抑制信号的汇编来调节。大多数T细胞的主要次级共刺激和共抑制信号分别是由CD28或CTLA-4传递的信号。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，作为推论，其他分子可能提供这些功能。这项资助建议通过产生不同的CEACAM1亚型来研究癌胚抗原相关细胞黏附分子1(CEACAM1)作为共抑制或共刺激分子的作用，这些亚型分别具有长或短的细胞质尾巴，这些亚型是通过交替剪接产生的。因此，我们提出了以下具体目标：(1)通过建立一种下调CEACAM1在T细胞中特异性表达的动物模型，将表达一条长(L)细胞质尾巴的CEACAM1定义为对T细胞的共同抑制分子，并从所涉及的配体和细胞内信号通路两个方面确定这种抑制的分子机制；(2)通过建立过表达CEACAM1亚型的转基因动物，以及在T细胞活化过程中CEACAM1-L和-S在T细胞中的表达特征，确定表达短(S)细胞质尾巴的CEACAM1亚型是否共同刺激了TcR/CD3复合体信号转导和肠道炎症的发生；以及(3)确定T细胞上的CEACAM1是否在其他细胞类型的负调控中发挥作用及其对接触性T和B细胞调节的意义。这些研究将确定CEACAM1是否是一种新的非CD28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.