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）：天然杀手（NK）细胞是先天免疫的重要效应细胞类型。鼠NK细胞使用一系列抑制性LY49受体，这些抑制性Ly49受体将“自我与”缺失。 NKG2D是一种主要的NK激活受体，与H60等配体相互作用。通过LY49介导的抑制作用被认为在全球范围内影响NK细胞功能。但是，尚未探索LY49决定特定效应函数的可能性。因此，提出LY49介导的抑制的强度将有助于确定效应函数的类型NK细胞执行。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受体之间信号传导强度的平衡的函数。为了定义“改变平衡”的现象，我们将H60用作NKG2D的激活配体，并分析了LY49/MHC和NKG2D/H60受体之间的相互作用。尽管我们的研究提供了平衡改变的坚定基础，但这种相互作用的许多方面尚未理解。因此，我们提出以下内容：在AIM 1中，我们将定义更改余量在确定选择性NKG2D介导的效应子功能（例如细胞毒性和细胞因子世代）中的作用。在AIM 2中，我们将使用另一种NKG2D激活配体RAE-1DELTA概括了变化的余量假设。在AIM 3中，我们将使用BCL10基因敲除动物来定义确定NK细胞选择性效应函数的信号事件，在该动物中我们观察到细胞因子分泌中的特定缺陷，但在细胞毒性中却没有。最后，在AIM 4中，我们将确定NK细胞膜平面上LY49C和内源性MHC之间CIS相互作用的分子机制及其功能后果。这里提出的旨在测试和完善变化平衡假设的实验应详细了解NK细胞如何测量环境信号并响应它们。这对于理解NK细胞的生物学很重要。这里确定的机制不仅将对肿瘤和移植物免疫具有实际影响，而且还将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性输入。