KIR and the Role of CD8 in NK Cell Function

KIR 和 CD8 在 NK 细胞功能中的作用

• 批准号: 6915448
• 负责人: LEWIS Lee LANIER
• 金额: $ 11.85万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6915448
• 关键词: CD8 molecule; MHC class I antigen; biological signal transduction; cell biology; cell line; clinical research; cytolysis; human subject; immunologic receptors; mixed tissue /cell culture; monoclonal antibody; natural killer cells; protein structure function

NK cells play a pivotal role bridging the innate and adaptive immune systems and have been implicated in protection against pathogens and tumors. Contrary to prior expectations, recent studies have revealed that NK cells express a sophisticated and diverse system of inhibitory and activating receptors that regulate their behavior. Moreover, these receptors are rapidly evolving, presumably in response to pathogens as well as to newly arising polymorphisms in the host's MHC. The studies proposed in this application focus on the role of CD8alpha in human NK cell recognition of MHC class I and on the signaling and function of human KIR2DL4, a unique member of the human KIR gene family. Mouse NK cell do not express CD8 nor do mice possess KIR genes. The goal of specific aim 1 is to determine the functional significance of CD8alpha expression on human NK cells. The hypothesis to be tested is that human CD8a functions as a co-stimulatory or coinhibitory receptor for an activating or inhibitory KIR, respectively. We will also test the hypothesis that CD8alpha is more critical when low affinity KIR ligands are being recognized. The objective of specific aim 2 is to define the signaling pathway and functional properties of the human KIR2DL4 molecule. The hypothesis to be tested is that a novel signaling adapter protein is required for KIR2DL4 function. Furthermore, we propose that the downstream transcriptional targets of KIR2DL4 signaling will differ from other KIR2DS or KIR3DS activating receptors, which in turn will result in different biological outcomes. Therefore, our studies promise to provide new insights into immune recognition by human NK cells that cannot be readily addressed in mouse models. Our findings may have relevance to understanding the role of human NK cells and their receptors in infectious disease, cancer and autoimmunity.

NK 细胞在连接先天性免疫系统和适应性免疫系统中发挥着关键作用，并与抵抗病原体和肿瘤有关。与之前的预期相反，最近的研究表明 NK 细胞表达复杂且多样化的抑制和激活受体系统，调节其行为。此外，这些受体正在快速进化，可能是对病原体以及宿主 MHC 中新出现的多态性的反应。本申请中提出的研究重点关注 CD8α 在人类 NK 细胞识别 I 类 MHC 中的作用以及人类 KIR2DL4（人类 KIR 基因家族的独特成员）的信号传导和功能。小鼠 NK 细胞不表达 CD8，小鼠也不表达 KIR 基因。具体目标 1 的目标是确定 CD8α 表达对人类 NK 细胞的功能意义。要测试的假设是人类 CD8a 分别作为激活或抑制 KIR 的共刺激或共抑制受体。我们还将检验以下假设：当识别低亲和力 KIR 配体时，CD8α 更为关键。 具体目标 2 的目的是定义人类 KIR2DL4 分子的信号通路和功能特性。要测试的假设是 KIR2DL4 功能需要一种新的信号转导接头蛋白。此外，我们认为 KIR2DL4 信号传导的下游转录靶标将不同于其他 KIR2DS 或 KIR3DS 激活受体，这反过来将导致不同的生物学结果。因此，我们的研究有望为人类 NK 细胞的免疫识别提供新的见解，而这在小鼠模型中是无法轻易解决的。我们的研究结果可能有助于了解人类 NK 细胞及其受体在传染病、癌症和自身免疫性疾病中的作用。