NK Cell Biology

摘要 表达在T细胞和NK细胞上的激活的NKG2D受体识别 与主要配体具有结构同源性的多基因和多态的配体家族 组织相容性复合体I类蛋白。这些配体没有表达或正在表达 在成年人的健康组织中只有少量表达，但它们经常过量表达。 由肿瘤表达，在感染病毒和细菌后上调，以及 在某些自身免疫性疾病组织中被检测到。虽然NKG2D 配体通常在细胞表面以跨膜锚定或 糖基磷脂酰肌醇(GPI)锚定蛋白，其中一些配体包括 云母、MICB和ULBP-2可以从肿瘤细胞分泌或脱落。这些 在人类癌症患者的血清中经常检测到可溶性NKG2D配体， 从而导致假设它们可能允许肿瘤逃脱NKG2D介导的 作为NKG2D的诱饵配体的免疫应答。这个项目的总体目标是 项目是确定NKG2D配体表达在自身免疫中的后果 疾病以及针对癌症和传染性疾病的先天和获得性免疫反应 疾病。为了实现这一目标，我们将开发新的鼠标型号，以帮助我们和 其他研究人员了解NKG2D配体的功能以及这些 功能可以调节，以减轻疾病。在目标1中，我们将建立小鼠，其中 细胞表面NKG2D配体RAE-1可以选择性地在任何细胞类型或 感兴趣的组织。最初，我们将利用这些小鼠在胰岛上特异地表达RAE-1 以确定对自身免疫发育的影响， 另外，关于胰腺原发肿瘤的发展。在目标2中，这些小鼠将 在树突状细胞(DC)上表达RAE-1，以探讨这对交叉反应的影响。 DC、NK细胞和T细胞之间的对话。在目标3中，我们将表达一种可溶性的NKG2D 配体在转基因小鼠中系统地或以肿瘤细胞特异性的方式正式 解决可溶性NKG2D配体是否可以允许肿瘤免疫逃逸以及 可溶性NKG2D配体对病原体的免疫防御作用减弱。总而言之，这些 研究将为NKG2D及其配体在自身免疫中的作用提供新的见解 在宿主防御方面，他们将为临床前提供新的模型系统 以NKG2D通路为靶点治疗自身免疫疾病的研究进展 和癌症。

Abstract 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 NKG2Dligands 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.