Mechanisms of NK Cell Activation by the KIR2DL4 Receptor

KIR2DL4 受体激活 NK 细胞的机制

• 批准号: 7013613
• 负责人: Kerry S Campbell
• 金额: $ 27.06万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7013613
• 关键词: biological signal transduction; cell mediated cytotoxicity; clinical research; cytokine; human tissue; interferon gamma; leukocyte activation /transformation; natural killer cells; protein structure function; receptor expression

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?

描述（由申请人提供）：KIR2DL4（2DL4; CD158D）在人类的杀手细胞Ig样受体（KIR）家族中在结构和功能上是独一无二的。研究表明，2DL4是在所有分析的NK细胞克隆中表达mRNA的唯一KIR，这强烈表明它具有生物学上重要的功能。据报道，它也是唯一结合HLA-G的KIR，它几乎完全在胎儿衍生的滋养层细胞上表达，这些滋养细胞渗透了孕妇的母体deciDUA。因此，尽管显然可以使用其他功能作用，尤其是在癌症和病毒感染中，但已提出2DL4在怀孕期间发挥重要作用。 2DL4也是唯一的NK细胞激活受体，据报道会触发干扰素（IFN）γ的产生，但不靶向静止的人NK细胞中的细胞毒性。相比之下，其他NK细胞激活受体启动了一个功能反应程序，该程序均导致IFNGAMMA产生和细胞毒性。我们假设2DL4的独特功能属性是由物理连接到独特的跨膜辅助蛋白而引起的，该蛋白将受体耦合到与其他激活受体触发的级联的信号转导级联有关。我们的初步数据支持这一假设。我们建议定义由2DL4激活的独特功能响应程序的分子基础，并定义与其他NK细胞激活受体触发的元素，这些元素也刺激了细胞溶解反应。结果将使我们能够定义分子基础，以激活NK细胞中不同的功能反应程序，当它们遇到滋养细胞，肿瘤细胞或感染病毒感染细胞时。我们将追求以下具体目标以实现这一目标： 1 KIR2DL4的结构元素如何促进其独特的功能？ 2。哪些附件信号蛋白与KIR2DL4的跨膜结构域有关，以传递细胞内信号？ 3。kiR2DL4传递独特的激活信号的非人类NK细胞的分子机制是什么？