Molecular Mechanisms of Natural Killer Cell Activation

自然杀伤细胞激活的分子机制

基本信息

批准号：
7650427
负责人：
Subramaniam Malarkannan
金额：
$ 32.97万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7650427
关键词：
Activated Natural Killer Cell Affect Amino Acids Animal Model Animals B-Lymphocytes Binding Biochemical Biological Models Biology Cell membrane Cell physiology Cells Cellular biology Complex Cues Cytolysis Cytoplasmic Tail Data Decision Making Defect Dendritic Cells Down-Regulation Effector Cell Equilibrium Event Family member Generations Histocompatibility Antigens Class I Immunity Immunotherapeutic agent Individual Investigation KLRA1 gene Lead Ligands Lymphocyte MHC Class I Genes MHC Interaction Maps Measures Mediating Membrane Membrane Microdomains Modeling Molecular Mus NK Cell Activation Natural Immunity Natural Killer Cells Nature Outcome Pathway interactions Pattern Play Principal Investigator Proliferating Protein Family Proteins Regulation Research Personnel Role Signal Transduction Signaling Molecule Site-Directed Mutagenesis Staining method Stains Stress System Testing base cell type chemokine cytokine cytotoxicity in vivo knockout animal macrophage meetings neoplastic cell novel programs receptor research study stable cell line tumor

项目摘要

DESCRIPTION (provided by applicant): Natural Killer (NK) cells are an important effector cell type of innate immunity. Murine NK cells use an array of inhibitory Ly49 receptors that discriminate 'self from 'missing-self. NKG2D is a major NK activating receptor that interacts with ligands such as H60. Inhibitions mediated through the Ly49 are thought to globally affect the NK cell functions. However, the possibility of Ly49 dictating specific effector functions has not been explored. Therefore, propose that the strength of the Ly49-mediated inhibition would help determine the type of effector functions NK cells to perform. Towards understanding this interplay, we hypothesized that NKG2D-mediated activation is a function of altering the balance in the signaling strength between the activating NKG2D and inhibiting Ly49 receptors. To define this phenomenon of 'altered- balance', we used H60 as the activating ligand for NKG2D and analyzed the interplay between Ly49/MHC and NKG2D/H60 receptors. Although, our studies provided a firm basis of altered balance, there are many aspects of this interplay that are not yet understood. Therefore, we propose the following: In Aim 1, we will define the role of altered-balance in determining selective NKG2D-mediated effector functions such as cytotoxicity and cytokine generations. In Aim 2, we will generalize the altered-balance hypothesis using another NKG2D activating ligand Rae-1delta. In Aim 3 we will define the signaling events that determine selective effector functions of NK cells using Bcl10 knockout animals where we observed a specific defect in the cytokine secretion but not in cytotoxicity. Finally, in Aim 4, we will determine the molecular mechanism of cis interaction between the Ly49C and the endogenous MHC on the plane of NK cell membrane and its functional consequences. The experiments proposed here to test and refine the altered-balance hypothesis should provide a detailed understanding of how NK cell can measure environmental signals and respond to them. This is important for the understanding of the biology of NK cells. Mechanisms identified here will not only have practical implications in tumor and graft immunity but will serve as models for other systems in which the responding cell must balance a number of activating and inhibitory inputs.

描述（由申请人提供）：自然杀伤（NK）细胞是先天免疫的重要效应细胞类型。小鼠 NK 细胞使用一系列抑制性 Ly49 受体来区分“自我”和“缺失的自我”。 NKG2D 是一种主要的 NK 激活受体，可与 H60 等配体相互作用。通过 Ly49 介导的抑制被认为会全面影响 NK 细胞功能。然而，Ly49 决定特定效应器功能的可能性尚未被探索。因此，建议 Ly49 介导的抑制强度将有助于确定 NK 细胞执行的效应功能类型。为了理解这种相互作用，我们假设 NKG2D 介导的激活是改变激活 NKG2D 和抑制 Ly49 受体之间信号强度平衡的功能。为了定义这种“平衡改变”现象，我们使用 H60 作为 NKG2D 的激活配体，并分析了 Ly49/MHC 和 NKG2D/H60 受体之间的相互作用。尽管我们的研究为改变平衡提供了坚实的基础，但这种相互作用的许多方面尚不清楚。因此，我们提出以下建议：在目标 1 中，我们将定义平衡改变在确定选择性 NKG2D 介导的效应功能（例如细胞毒性和细胞因子生成）中的作用。在目标 2 中，我们将使用另一种 NKG2D 激活配体 Rae-1delta 来推广平衡改变假说。在目标 3 中，我们将使用 Bcl10 敲除动物来定义决定 NK 细胞选择性效应功能的信号事件，在这些动物中我们观察到细胞因子分泌的特定缺陷，但未观察到细胞毒性的特定缺陷。最后，在目标 4 中，我们将确定 NK 细胞膜平面上 Ly49C 与内源性 MHC 之间顺式相互作用的分子机制及其功能后果。这里提出的测试和完善平衡改变假设的实验应该可以详细了解 NK 细胞如何测量环境信号并对其做出反应。这对于理解 NK 细胞的生物学非常重要。这里确定的机制不仅对肿瘤和移植物免疫具有实际意义，而且可以作为其他系统的模型，在这些系统中，响应细胞必须平衡许多激活和抑制输入。