NK Cell Receptors and Their Ligands

我们实验室的中心重点是确定负责NK细胞识别的机制， 确定NK细胞受体及其配体在抗病毒感染细胞和肿瘤免疫中的作用。 在这次竞争性续期申请中，我们建议继续努力实现这一目标， 人类和小鼠NK细胞生物学的三个有前途的新领域。具体目标是：（1）确定如何 小鼠NK细胞使用激活的Ly 49 P受体识别巨细胞病毒（CMV）感染的细胞， 提供保护性抗病毒免疫，2）确定激活人NK细胞受体的特异性， 由病毒感染的细胞和树突状细胞呈递的配体，和3）为了评估由病毒感染的细胞和树突状细胞呈递的配体的功能， 人NKR-P1 A受体及其配体。对于目标1，我们有初步数据显示， 抗MCMV MA/My小鼠NK细胞表达的Ly 49 P受体识别MCMV感染的细胞， 只有当MCMV感染的细胞首次表达H-2k时，NK细胞对细胞的识别才能被证明是正确的。 病原体可能是MHC限制性的。我们概述了定义这种体外识别机制的策略， vivo.对于aim 2，我们已经建立了一个强大的新的基于功能的表达克隆策略， 验证了其在鉴定人EBV转化的B细胞上激活人NK细胞的配体中的用途。 我们现在将使用这种策略来阐明人NK细胞如何识别人CMV感染的细胞， 人NK细胞与树突状细胞相互作用在最后的目标中，我们最近确定了一种配体， 人NKR-P1 A（CD 161）受体，并将进行研究，以确定功能和信号转导， 从这种受体-配体相互作用。总的来说，这个项目将进一步加深我们对鼠标 而人NK细胞有助于抵抗病毒感染的细胞和肿瘤的免疫。

The central focus of our lab is to define the mechanisms responsible for NK cell recognition, and to determine the role of NK cell receptors and their ligands in immunity against virus-infected cells and tumors. In this competitive renewal application, we propose to continue our efforts towards this goal by addressing three promising new areas in human and mouse NK cell biology. Specific aims are: 1) To determine how mouse NK cells use the activating Ly49P receptor to recognize cytomegalovirus (CMV)-infected cells and provide protective anti-viral immunity, 2) To define the specificities of activating human NK cell receptors for ligands presented by virus-infected cells and by dendritic cells, and 3) To evaluate the function of the human NKR-P1A receptor and its ligand. For aim 1, we have preliminary data showing that the activating Ly49P receptor express by NK cells in MCMV-resistant MA/My mice recognizes MCMV-infected cells, but only if the MCMV-infected cells express H-2k suggeting for the first time that NK cell recognition of a pathogen may be MHC-restricted. We outline strategies to define this mechanism of recognition in vitro and vivo. For aim 2, we have established a powerful new function-based expression cloning strategy, and have validated its use in identifying ligands on human EBV-transformed B cells that activated human NK cells. We will now use this strategy to elucidate how human NK cells recognize human CMV-infected cells and how human NK cell interact with dendritic cells. In the final aim, we have recently identified a ligand for the human NKR-P1A (CD161) receptor, and will conduct studies to define the function and signaling resulting from this receptor-ligand interaction. Collectively, this project will further our understanding of how mouse and human NK cells contribute to immunity againts virus-infected cells and tumors.