NK Cell Biology

描述(申请人提供)：表达在T细胞和NK细胞上的激活的NKG2D受体识别与主要组织相容性复合体I类蛋白结构同源的多基因和多态的配体家族。这些配体在成人的健康组织中不表达或只有少量表达，但它们经常在肿瘤中过度表达，在感染病毒和细菌后上调，并在某些自身免疫性疾病组织中检测到。尽管NKG2D配体通常以跨膜锚定或糖基化磷脂酰肌醇(GPI)锚定蛋白的形式在细胞表面表达，但其中一些配体，包括MICA、MICB和ULBP-2，可以从肿瘤细胞中分泌或脱落。这些可溶性的NKG2D配体经常在人类癌症患者的血清中检测到，这导致了一种假设，即它们可能通过作为NKG2D的诱饵配体而使肿瘤逃脱NKG2D介导的免疫反应。该项目的总体目标是确定NKG2D配体表达在自身免疫性疾病以及针对癌症和传染病的先天性和获得性免疫反应中的后果。为了实现这一目标，我们将开发新的小鼠模型，帮助我们和其他研究人员了解NKG2D配体的功能，以及如何调节这些功能来缓解疾病。在目标1中，我们将建立细胞表面NKG2D配体RAE-1可以在任何感兴趣的细胞类型或组织中选择性表达的小鼠。最初，我们将利用这些小鼠在胰腺中的胰岛细胞上特异性地表达RAE-1，以确定其对自身免疫发展的影响，以及对原发胰腺肿瘤发展的影响。在目标2中，这些小鼠将被用来在树突状细胞(DC)上表达RAE-1，以探索这如何影响DC、NK细胞和T细胞之间的相互作用。在目标3中，我们将在转基因小鼠中系统地表达可溶性NKG2D配体，或者以肿瘤细胞特异性的方式表达，以正式研究可溶性NKG2D配体是否可以允许肿瘤的免疫逃逸，以及可溶性NKG2D配体是否损害对病原体的免疫防御。总的来说，这些研究将为NKG2D及其配体在自身免疫和宿主防御中的作用提供新的见解，并将为针对NKG2D途径治疗自身免疫和癌症的治疗的临床前评估提供新的模型系统。 公共卫生相关性：NKG2D是一种白细胞(NK细胞和T细胞)上的受体，已被证明可提供对病原体和肿瘤的保护性免疫，并与骨髓和心脏移植的排斥反应以及某些自身免疫性疾病有关，包括类风湿性关节炎、乳糜泻和I型糖尿病。在这个项目中，我们建议开发新的小鼠模型系统，在其中我们可以研究肿瘤如何试图逃避NKG2D受体的检测，以及NKG2D受体在宿主抗肿瘤反应和自身免疫中的重要性。

DESCRIPTION (provided by applicant): The activating NKG2D receptor expressed on T cells and NK cells recognizes a polygenic and polymorphic family of ligands with structural homology to major histocompatibility complex class I proteins. These ligands are not expressed or are expressed in only low amounts by healthy tissues of adults, but they are frequently over- expressed by tumors, are up-regulated after infection with viruses and bacteria, and have been detected in certain autoimmune diseased tissues. Although the NKG2D ligands are typically expressed on the cell surface as transmembrane-anchored or glycosylphosphatidylinositol (GPI)-anchored protein, some of these ligands, including MICA, MICB, and ULBP-2, can either be secreted or shed from tumor cells. These soluble NKG2D ligands are frequently detected in the sera of human cancer patients, leading to the hypothesis that they may allow tumors to escape NKG2D-mediated immune responses by serving as decoy ligands for NKG2D. The overall goal of this project is to determine the consequences of NKG2D ligand expression in autoimmune diseases and in innate and adaptive immune responses against cancer and infectious diseases. To meet this goal, we will develop new mouse models that will help us and other investigators to understand the functions of NKG2D ligands and how these functions can be regulated to relieve disease. In aim 1, we will establish mice in which a cell surface NKG2D ligand, Rae-1, can be selectively expressed in any cell type or tissue of interest. Initially, we will use these mice to express Rae-1 exclusively on islet cells in the pancreas to determine the impact on the development of autoimmunity and, separately, on the development of primary pancreatic tumors. In aim 2, these mice will be used to express Rae-1 on dendritic cells (DC) to explore how this impacts the cross- talk between DC, NK cells, and T cells. In aim 3, we will express a soluble NKG2D ligand systemically in transgenic mice or in a tumor cell-specific manner to formally address whether soluble NKG2D ligands can allow immune evasion by tumors and if soluble NKG2D ligands impair immune defense against pathogens. Collectively, these studies will provide new insights into the role of NKG2D and its ligands in autoimmunity and in host defense, and they will provide new model systems for the pre-clinical evaluation of therapeutics targeting the NKG2D pathway for treatment of autoimmunity and cancer. PUBLIC HEALTH RELEVANCE: NKG2D is a receptor on a class of white blood cells (NK cells and T cells) that has been demonstrated to provide protective immunity against pathogens and tumors, as well as implicated in the rejection of bone marrow and heart transplants and in certain autoimmune diseases, including rheumatoid arthritis, celiac disease, and type I diabetes. In this project, we propose to develop new mouse model systems in which we can study how tumors attempt to evade detection by the NKG2D receptor, and the importance of the NKG2D receptor in the host response against tumors and autoimmunity.