KIR and the Role of CD8 in NK Cell Function

NK细胞在连接先天免疫系统和适应性免疫系统中发挥着关键作用，并参与了对病原体和肿瘤的保护。与先前的预期相反，最近的研究表明，NK细胞表达一种复杂多样的抑制和激活受体系统，调节其行为。此外，这些受体正在迅速进化，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集中于CD8 α在人NK细胞识别MHC I类中的作用以及人KIR 2DL4（人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，也不具有 KIR基因。具体目标1的目的是确定人NK细胞上CD8 α表达的功能意义。待检验的假设是人CD8a分别作为活化或抑制性KIR的共刺激或共抑制受体发挥功能。我们还将测试的假设，即CD8 α是更关键的低亲和力KIR配体被识别。 具体目标2的目的是确定人KIR2DL4分子的信号传导途径和功能特性。待检验的假设是KIR2DL4功能需要新的信号传导衔接蛋白。此外，我们提出KIR2DL4信号传导的下游转录靶点将不同于其他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，而这在小鼠模型中无法轻易解决。我们的研究结果可能与理解人类NK细胞及其受体在感染性疾病，癌症和自身免疫中的作用有关。

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.