Mechanisms of NK Cell Activation by the KIR2DL4 Receptor

描述(申请人提供)：KIR2DL4(2DL4；CD158d)在人类杀伤细胞Ig样受体(KIR)家族成员中在结构和功能上是独一无二的。研究表明，2DL4是在所分析的所有NK细胞克隆中唯一表达其mRNA的KIR，这有力地表明了它具有重要的生物学功能。它也是据报道唯一与人类白细胞抗原-G结合的KIR，人类白细胞抗原-G几乎只在胎儿来源的滋养层细胞上表达，这些细胞渗透到孕妇的母体蜕膜中。因此，2DL4已被认为在妊娠期间发挥重要作用，尽管其他功能显然是可能的，特别是在癌症和病毒感染中。 2DL4也是唯一的NK细胞激活受体，据报道可以在静息的人NK细胞中触发干扰素(IFN)的产生，但不会对靶细胞产生细胞毒作用。相反，其他NK细胞激活受体启动功能反应程序，导致干扰素-γ产生和细胞毒性。我们推测，2DL4独特的功能属性源于与一种独特的跨膜辅助蛋白的物理连接，该辅助蛋白将受体连接到不同于其他激活受体触发的信号转导级联。我们的初步数据支持这一假设。我们建议定义2DL4激活的独特功能反应程序的分子基础，并定义与其他NK细胞激活受体所触发的不同的元件，这些元件也刺激细胞溶解反应。这一结果将使我们能够确定当NK细胞遇到滋养层细胞、肿瘤细胞或病毒感染细胞时，激活NK细胞不同功能反应程序的分子基础。为实现这一目标，我们将实现以下具体目标： 1 KIR2DL4的结构元素如何促成其独特的功能？ 2.什么辅助信号蛋白与KIR2DL4的跨膜区相关，以转导细胞内信号？ 3.KIR2DL4转导人类NK细胞独特的激活信号的分子机制是什么？

DESCRIPTION (provided by applicant): KIR2DL4 (2DL4; CD158d) is structurally and functionally unique among members of the killer cell Ig-like receptor (KIR) family in humans. Studies indicate that 2DL4 is the only KIR for which mRNA is expressed in all NK cell clones analyzed, which strongly indicates that it serves a biologically important function. It is also the only KIR that reportedly binds HLA-G, which is almost exclusively expressed on fetal-derived trophoblasts that infiltrate the maternal decidua in pregnant women. Thus, 2DL4 has been proposed to play an important role during pregnancy, although additional functional roles are clearly possible, particularly in cancer and virus infection. 2DL4 also stands out as the only NK cell activating receptor that reportedly triggers interferon (IFN)gamma production, but not target cell cytotoxicity in resting human NK cells. In contrast, other NK cell activating receptors initiate a functional response program that leads to both IFNgamma production and cytotoxicity. We hypothesize that the distinctive functional attributes of 2DL4 result from physical linkage to a unique transmembrane accessory protein that couples the receptor to signal transduction cascades that differ from those triggered by other activating receptors. Our preliminary data support this hypothesis. We propose to define the molecular basis for the distinctive functional response program activated by 2DL4 and define the elements that differ from those triggered by other NK cell activating receptors that also stimulate cytolytic responses. The results will allow us to define the molecular basis for activating distinct functional response programs in NK cells when they encounter trophoblasts, tumor cells, or virus infected cells. We will pursue the following specific aims to achieve this goal: 1 How do structural elements of KIR2DL4 contribute to its unique functions? 2. What accessory signaling protein is associated with the transmembrane domain of KIR2DL4 to transduce intracellular signals? 3. What are the molecular mechanisms by which KIR2DL4 transduces unique activation signals inhuman NK cells?