Regulation of Mucosal Lymphocytes

描述(申请人提供)：适当调节先天和获得性免疫反应对于维持肠道组织的动态平衡和使免疫反应关闭以恢复平衡至关重要，一旦炎症的要求结束并需要修复，如炎症性肠病(IBD)。这项研究建议解决了一个悬而未决的问题，即癌胚抗原细胞黏附分子1(CEACAM1)是如何调节的，进而调节肠道免疫反应。我们的长期目标是了解他的知识如何应用于IBD的治疗。本研究的目的是了解CEACAM1亚型通过交替剪接在粘膜组织中的表达是如何调节的，这些亚型如何在维持体内平衡或调节炎症方面发挥作用，以及涉及的特定细胞内信号通路。核心假设是CEACAM1亚型的水平和类型直接受共生微生物区系控制，这些异构体的信号与不同的功能结果相关，这些功能结果具有共同的性质，即通过直接抑制免疫受体信号(CEACAM1-L)或通过诱导独特类型的调节途径(例如CD_4+LAP+T细胞)或过程(例如IgA产生)间接调节粘膜淋巴细胞功能。其基本原理源于一种新兴的观点，即CEACAM1-Long(L)和-Short(S)亚型在T细胞中的相对表达分解成一个可调节的系统，调节T细胞的整体功能特性。在大量初步数据的指导下，中心假说将在三个具体目标上得到验证：1)确定CEACAM1在粘膜组织中的表达是如何调节的；2)确定CEACAM1在影响粘膜组织中的动态平衡和炎症方面的生理功能；3)阐明CEACAM1-S信号的机制以及CEACAM1-L对其的调控。在目标1中，我们试图了解共生微生物区系和耐受信号(T细胞受体/CD3复合信号)调节CEACAM1表达、剪接和对抗原的反应的机制(S)。在目的2中，利用新建立的Ceacam1-/-小鼠和在T细胞中有条件地转基因表达特定类型的CEACAM1-亚型的小鼠，我们试图了解CEACAM1调节动态平衡的机制。在目标3中，我们将确定CEACAM1-S信号的特定细胞内途径，并确定CEACAM1-L亚型如何调节这一信号通路，以及靶向诱导调节性T细胞的可能性。总体而言，这项建议将深入了解CEACAM1功能的基本机制，这一点具有重要意义，因为它将阐明CEACAM1由本土环境因素调节，以及这种调节如何导致维持粘膜动态平衡和控制肠道炎症和其他病理过程。这些知识有望确定针对免疫系统的新策略，以抑制炎症或增强抗肿瘤和抗感染免疫。

DESCRIPTION (provided by applicant): Proper regulation of innate and adaptive immune responses is critical for the maintenance of homeostasis in intestinal tissues and in bringing an immune response to closure in order to restore balance once the requirement for inflammation is ended and repair required such as in inflammatory bowel disease (IBD). This research proposal addresses the unanswered question of how carcinoembryonic antigen cell adhesion molecule 1 (CEACAM1) is regulated and in turn regulates intestinal immune responses. Our long-term go`al is to understand how his knowledge can be utilized in the treatment of IBD. The objective of this research is to understand how CEACAM1 isoform expression through alternate splicing is regulated in mucosal tissues, how these isoforms function in the maintenance of homeostasis or regulation of inflammation and the specific intracellular signaling pathways involved. The central hypothesis is that the level and types of CEACAM1 isoforms are directly controlled by the commensal microbiota and that the signaling from these isoforms are associated with distinct functional outcomes that have the common property of maintaining homeostasis through either direct inhibition of immune receptor signaling (CEACAM1-L) or indirect regulation of mucosal lymphocyte function via the induction of unique types of regulatory pathways (e.g. CD4+LAP+ T cells) or processes (e.g. IgA production). The rationale is derived from the emerging view that the relative expression of CEACAM1-long (L) and -short (S) isoforms in a T cell resolves into a tunable system that regulates the overall functional properties of a T cell. Guided by extensive preliminary data, the central hypothesis will be tested in three specific aims: 1) Determine how CEACAM1 expression is regulated in mucosal tissues; 2) Define the physiologic functions of CEACAM1 in influencing homeostasis versus inflammation in mucosal tissues, and; 3) Elucidate the mechanism(s) of CEACAM1-S signaling and its regulation by CEACAM1-L. In Aim 1, we seek to understand the mechanism(s) by which commensal microbiota and tolerogenic signals (T cell receptor/CD3 complex signaling) regulate CEACAM1 expression, splicing and responses to antigen. In Aim 2, using newly created Ceacam1-/- mice and mice with conditional transgenic expression of specific types of CEACAM1- isoforms in T cells, we seek to understand the mechanisms by which CEACAM1 regulates homeostasis. In Aim 3, we will determine the specific intracellular pathway of CEACAM1-S signaling and define how this is regulated by CEACAM1-L isoforms and the potential for targeted induction of regulatory T cells. Overall, this proposal will gain insights into the fundamental mechanisms of CEACAM1 function, which is significant because it will elucidate CEACAM1 regulation by indigenous environmental factors and the manner in which this regulation results in the maintenance of mucosal homeostasis and the control of intestinal inflammation and other pathologic processes. Such knowledge is expected to identify new strategies for targeting the immune system in the goal of inhibiting inflammation or enhancing anti-tumor and anti-infective immunity.