NK Cell Biology

摘要 在T细胞和NK细胞上表达的活化NKG 2D受体可识别 与主要配体具有结构同源性的多基因多态配体家族 组织相容性复合物I类蛋白。这些配体不表达或 在成年人的健康组织中仅少量表达，但它们经常过度表达。 由肿瘤表达，在病毒和细菌感染后上调， 在某些自身免疫性疾病组织中被检测到。虽然NKG 2D 配体通常以跨膜锚定的形式表达在细胞表面上， 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 可溶性NKG 2D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，即它们可能允许肿瘤逃避NKG 2D介导的 免疫应答，作为NKG 2D的诱饵配体。这个项目的总体目标是 该项目旨在确定NKG 2D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适应性免疫应答 疾病为了实现这一目标，我们将开发新的小鼠模型，这将帮助我们， 其他研究人员了解NKG 2D配体的功能，以及这些配体是如何发挥作用的。 可以调节功能以缓解疾病。在目标1中，我们将建立小鼠， 细胞表面NKG 2D配体Rae-1可以在任何细胞类型中选择性表达， 感兴趣的组织。最初，我们将使用这些小鼠专门在胰岛上表达Rae-1， 胰腺中的细胞，以确定对自身免疫发展的影响， 分别对原发性胰腺肿瘤的发展。在目标2中，这些小鼠将 用于在树突状细胞（DC）上表达Rae-1，以探索这如何影响交叉免疫。 DC、NK细胞和T细胞之间的对话。在目标3中，我们将表达可溶性NKG 2D， 在转基因小鼠中或以肿瘤细胞特异性方式全身性地给予配体， 解决可溶性NKG 2D配体是否可以允许肿瘤的免疫逃避， 可溶性NKG 2D配体损害针对病原体的免疫防御。总的来说，这些 研究将为NKG 2D及其配体在自身免疫中的作用提供新的见解 和宿主防御，它们将为临床前 评价靶向NKG 2D通路治疗自身免疫性疾病的疗法 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.