"Innate Immune Lymphocytes and the Gut Epithelium"

摘要：在复杂生物体中，肠道上皮隔室的主要功能是提供一个保护屏障，防止病原生物通过胃肠道进入，并促进所需营养物质的吸收和分布。这些功能是由许多不同但相互作用的细胞类型（包括上皮细胞、基质细胞和免疫系统细胞）的协同作用完成的。不同的细胞类型在结构上组织和功能上产生一个工作的组织系统，可以提供这些主要功能并有助于宿主的生存。我们的中心假设是，任何这些细胞类型的功能障碍都会对组织执行这些功能的能力产生不利影响。特别是，我们推断免疫系统细胞是肠道上皮功能的重要组成部分，它们不仅在宿主对肠道病原体的初始反应中发挥作用，而且可能通过释放可溶性介质和/或细胞间相互作用，在维持上皮的完整性和功能方面发挥作用。在这组研究中，我们将试图了解一个新的上皮内淋巴细胞亚群，？/d T细胞，有助于肠道上皮屏障的功能。提出了三个具体目标：1。使用基于表达的方法确定缺乏？的小鼠小肠中的特定基因和/或途径是否发生改变？/d T细胞。2. 基于Aim 1中获得的信息，讨论这些改变如何影响粘膜上皮的结构或功能。3. 确定是否缺乏？/d T细胞会影响宿主对肠道感染的反应成分。所描述的研究将为影响粘膜室的免疫和非免疫细胞类型之间复杂的相互关系提供基本见解，并确定受粘膜免疫室改变影响的途径。此外，这些研究将增加我们对？/d T细胞定位于肠道。此外，这些研究可能会确定特定的分子靶点，以对导致肠道感染易感性增加或介导免疫介导的组织损伤的疾病状态进行合理的治疗干预。人们对组成粘膜隔室的各种细胞类型如何相互作用以确保宿主存活非常感兴趣。这些功能包括作为抵御环境挑战（感染、毒素等）的屏障，允许必需营养物质的运输，并作为首次接触肠道病原体的场所。本应用程序中描述的研究利用小鼠系统来获得对一种新的常驻免疫细胞类型TCR ？/d T细胞，有助于肠上皮屏障的整体功能。这些研究可能会确定特定的分子靶点，以对导致肠道感染易感性增加或介导免疫介导的组织损伤的疾病状态进行合理的治疗干预

DESCRIPTION (provided by applicant): Abstract: The major functions of the gut epithelial compartment in a complex organism is to provide a protective barrier from pathogenic organisms that gain entry through the GI tract as well as facilitate the absorption and distribution of needed nutrients. These functions are accomplished by the concerted action of a number of diverse yet interacting cell types including epithelial cells, stromal elements and cells of the immune system. The varied cell types are structurally organized and function to produce a working tissue system that can provide these major functions and contribute to host survival. Our central hypothesis is that dysfunction of any of these cell types will have adverse effects on the capacity of the tissue to carry out these functions. In particular, we reason that cells of the immune system are an essential component for the functioning of the gut epithelia and they not only play a role in the initial host response to enteric pathogens but also are likely to function, through the release of soluble mediators and/or cell-cell interactions, in the maintenance of the integrity and function of the epithelium. In this set of studies we will seek to understand how a novel subset of intraepithelial lymphocytes, ?/d T cells, contribute to the functioning of the gut epithelial barrier. Three specific aims are proposed: 1. Using an expression based approach determine if specific genes and/or pathways are altered in the small intestine of mice deficient in ?/d T cells. 2. Based on the information obtained in Aim 1, address how these alterations can impact on the structure or function of the mucosal epithelium. 3. Determine if the lack of ?/d T cells will have an impact on components of the host response to enteric infection. The described studies will provide basic insights into the complex interrelationship between immune and non-immune cells types that impact on the mucosal compartment and identify those pathways that are affected by an altered mucosal immune compartment. In addition these studies will increase our understanding of the immunobiology of ?/d T cells localized to the gut. Furthermore, these studies will likely identify specific molecular targets for rational therapeutic intervention of disease states that lead to either an increased susceptibility to enteric infection or mediate immune-mediated tissue damage. There is considerable interest in how the various cell types that compose the mucosal compartment interact so as to ensure the survival of the host. These functions include acting as a barrier form environmental challenges (infections, toxins, etc.), allowing for the transport of essential nutrients and serving as the site of first encounter with enteric pathogens. The studies described in this application utilize a mouse system to gain basic insights into how a novel resident immune cell type, the TCR ?/d T cell, contributes to the overall function of the intestinal epithelial barrier. These studies will likely identify specific molecular targets for rational therapeutic intervention of disease states that lead to either an increased susceptibility to enteric infection or mediate immune-mediated tissue damage