Regulation of Mucosal Lymphocytes

描述（由申请人提供）：先天性和适应性免疫应答的适当调节对于维持肠组织中的稳态以及使免疫应答关闭以在炎症需求结束并需要修复（例如在炎性肠病（IBD）中）时恢复平衡至关重要。这项研究提案解决了癌胚抗原细胞粘附分子1（CEACAM 1）如何调节并进而调节肠道免疫反应的未回答的问题。我们的长期目标是了解他的知识如何用于IBD的治疗。本研究的目的是了解如何通过选择性剪接CEACAM 1亚型表达在粘膜组织中进行调节，这些亚型如何在维持稳态或调节炎症以及参与的特定细胞内信号通路中发挥作用。中心假设是CEACAM 1同种型的水平和类型直接受肠道微生物群控制，并且来自这些同种型的信号传导与不同的功能结果相关，这些功能结果具有通过直接抑制免疫受体信号传导或通过免疫受体信号传导维持稳态的共同性质。（CEACAM 1-L）或通过诱导独特类型的调节途径间接调节粘膜淋巴细胞功能在一些实施方案中，免疫调节剂可以是免疫调节剂（例如，CD 4 + T细胞）或过程（例如，伊加产生）。基本原理来自于新兴的观点，即T细胞中CEACAM 1-长（L）和-短（S）同种型的相对表达分解成调节T细胞的整体功能特性的可调系统。在广泛的初步数据的指导下，将在三个特定目标中检验中心假设：1）确定CEACAM 1表达在粘膜组织中是如何调节的; 2）定义CEACAM 1在影响粘膜组织中的稳态与炎症方面的生理功能; 3）阐明CEACAM 1-S信号传导及其受CEACAM 1-L调节的机制。在目的1中，我们试图了解肠道微生物群和致耐受性信号（T细胞受体/CD 3复合物信号传导）调节CEACAM 1表达、剪接和对抗原的应答的机制。在目标2中，使用新创建的Ceacam 1-/-小鼠和T细胞中特定类型的CEACAM 1-同种型的条件性转基因表达的小鼠，我们试图了解CEACAM 1调节稳态的机制。在目标3中，我们将确定CEACAM 1-S信号传导的特异性细胞内途径，并确定CEACAM 1-L亚型如何调控这一途径，以及靶向诱导调节性T细胞的潜力。总的来说，该提案将深入了解CEACAM 1功能的基本机制，这是重要的，因为它将阐明CEACAM 1通过固有环境因素的调节以及这种调节导致维持粘膜稳态和控制肠道炎症和其他病理过程的方式。这些知识有望确定靶向免疫系统的新策略，以抑制炎症或增强抗肿瘤和抗感染免疫力。

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.