Defining extrinsic and intrinsic factors that differentially regulate migratory properties, cytokine/chemokine production, cytolytic function of NK cells

定义差异调节 NK 细胞迁移特性、细胞因子/趋化因子产生、溶细胞功能的外在和内在因素

• 批准号: RGPIN-2014-04775
• 负责人: Kung, Sam
• 金额: $ 2.99万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2014
• 资助国家: 加拿大
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=566732
• 关键词: Defining; extrinsic; intrinsic; factors; differentially

Natural Killer (NK) cells are bone marrow derived cells that constitute 10-15% of blood lymphocytes. They migrate to peripheral sites to inflamed lymph nodes to exert their immune-surveillance functions. Activation of NK has been studied mostly by its established effector functions, such as cytotoxicity activity and/or signature cytokine (IFN-g, TNF) responses. Recent data from my laboratory and others, however, showed that these effector functions could be regulated independently via different signaling pathways. The underlying molecular mechanisms that regulated various NK functions i.e. migration, cytotoxicity, chemokine/cytokine in specific microenvironment remain to be defined. To understand the NK-mediated immune network that co-ordinates multiple cellular components in responses to infections, my research program pursues the identification of extrinsic factors produced by microenvironments that direct intrinsic cellular factors to regulate various effector functions of NK cells at different maturation states. Based on the published and preliminary work in my laboratory, we developed an overarching hypothesis to be tested in this proposal: Helios and other Ikaros family members represent a new class of regulatory factor that determine differential NK effector functions upon NK activations. I described 4 independent but interconnected themes of studies that aimed to delineate, in short-term goals, how extrinsic factors (such as soluble factors from Toll-like receptor activated DC, Theme 1 and rare peptides, Theme 2), intrinsic factors (such as Helios and other Ikaros family members, Theme 3) and GM-CSF (Theme 4) regulate NK cell migration, cytotoxicity and chemokine/cytokine production. Theme 1. To define the effects of extrinsic factors, produced by activated DC, on the migratory properties of NK cells. We will test the sub-hypothesis that mature DC activated by different microbial agents produce different chemokines that regulate different NK cell migratory responses. Theme 2. To determine how extrinsic factors, such as rare peptide would influence the outcome of NK-mediated immune surveillance mechanism. We will test the sub-hypothesis that NK cells are activated by a putative receptor for the recognition of non-self, rare short peptides. Theme 3. To define the contribution of intracellular factors, such as gene-regulatory molecules, Helios and other Ikaros family members in shaping the functional outcomes of NK cell activation. We will test the sub-hypothesis that the expression level of individual Ikaros family member regulates different effector NK cell functions. Theme 4. To determine the molecular mechanisms underlying the effects of GM-CSF on NK cell repulsion and other effective functions. We will test the sub-hypothesis that GM-CSF induces chemo-repulsion of NK cells via JAK2-Stats signaling. The long term vision is to build a road map of how these factors regulate NK development and specific effector function at defined maturation or activation states. The novelty of the research project and the cutting edge technologies involved will create a rich environment for the training of HQP.

自然杀伤（NK）细胞是骨髓来源的细胞，占血液淋巴细胞的10-15%。它们会迁移到发炎的淋巴结的外周部位，以发挥其免疫监视功能。NK的活化主要通过其已建立的效应子功能来研究，例如细胞毒性活性和/或标志性细胞因子（IFN-g、TNF）应答。然而，我的实验室和其他实验室最近的数据表明，这些效应器功能可以通过不同的信号通路独立调节。在特定的微环境中，调节各种NK功能的潜在分子机制，即迁移、细胞毒性、趋化因子/细胞因子仍有待确定。为了了解NK介导的免疫网络，协调多个细胞成分对感染的反应，我的研究计划追求识别由微环境产生的外在因子，这些微环境指导内在细胞因子调节NK细胞在不同成熟状态下的各种效应子功能。基于在我的实验室中发表的和初步的工作，我们开发了一个总体假设，在这个提议中进行测试：Helios和其他Ikaros家族成员代表了一类新的调节因子，它们决定了NK激活后NK效应子的差异功能。我描述了4个独立但相互关联的研究主题，旨在描述在短期目标中，外在因素（如Toll样受体激活DC的可溶性因子，主题1和稀有肽，主题2），内在因素（如Helios和其他Ikaros家族成员，主题3）和GM-CSF（主题4）如何调节NK细胞迁移，细胞毒性和趋化因子/细胞因子产生。主题1.目的：明确活化DC产生的外源性因子对NK细胞迁移特性的影响。我们将测试的子假设，成熟的DC激活不同的微生物剂产生不同的趋化因子，调节不同的NK细胞迁移反应。主题2.探讨外源性因素如稀有肽对NK细胞免疫监视机制的影响。我们将检验NK细胞被假定的受体激活以识别非自身的罕见短肽的子假设。主题3.确定细胞内因子（如基因调控分子、Helios和其他Ikaros家族成员）在塑造NK细胞活化功能结果中的作用。我们将检验单个Ikaros家族成员的表达水平调节不同效应NK细胞功能的子假设。 主题4.目的：探讨GM-CSF对NK细胞的排斥作用及其他效应的分子机制。我们将检验GM-CSF通过JAK 2-Stats信号传导诱导NK细胞的化学排斥的子假设。长期的愿景是建立一个路线图，这些因素如何调节NK细胞的发展和特定的效应功能，在定义的成熟或激活状态。该研究项目的新奇和所涉及的尖端技术将为HQP的培训创造一个丰富的环境。