Mechanisms of NK Cell Activation by the KIR2DL4 Receptor

描述（由申请人提供）：KIR 2DL 4（2DL 4; CD 158 d）在人体杀伤细胞Ig样受体（KIR）家族成员中具有独特的结构和功能。研究表明，2DL 4是唯一的KIR，其mRNA在所分析的所有NK细胞克隆中表达，这强烈表明其具有生物学重要功能。据报道，它也是唯一结合HLA-G的KIR，HLA-G几乎仅在渗入孕妇母体蜕膜的胎儿来源的滋养层上表达。因此，2DL 4已被提出在妊娠期间发挥重要作用，尽管其他功能作用显然是可能的，特别是在癌症和病毒感染中。 2DL 4还作为据报道触发干扰素（IFN）γ产生但不触发静息人NK细胞中的靶细胞细胞毒性的唯一NK细胞活化受体而突出。相比之下，其他NK细胞活化受体启动导致IFN γ产生和细胞毒性的功能性应答程序。我们假设，2DL 4的独特的功能属性的结果从物理连接到一个独特的跨膜辅助蛋白，耦合受体的信号转导级联反应，从其他激活受体所触发的不同。我们的初步数据支持这一假设。我们建议定义由2DL 4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（也刺激细胞溶解反应）触发的不同的元素。这些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细胞中不同功能反应程序的分子基础。为实现这一目标，我们将努力实现以下具体目标： 1 KIR 2DL 4的结构元件如何有助于其独特的功能？ 2.什么辅助信号蛋白与KIR 2DL 4的跨膜结构域相关，以抑制细胞内信号？ 3. KIR 2DL 4在NK细胞中传递独特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?