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

自然杀伤细胞（NK）是骨髓来源的细胞，占血液淋巴细胞的10-15%。它们迁移到周围的炎症淋巴结，发挥其免疫监视功能。NK的活化主要通过其已建立的效应功能进行研究，如细胞毒性活性和/或特征细胞因子（IFN-g， TNF）反应。然而，我的实验室和其他人最近的数据表明，这些效应功能可以通过不同的信号传导途径独立调节。调控各种NK功能的潜在分子机制，即迁移、细胞毒性、趋化因子/细胞因子在特定微环境中的作用仍有待明确。为了了解NK介导的免疫网络，协调多种细胞成分对感染的反应，我的研究项目致力于识别微环境产生的外部因素，这些外部因素指导细胞内在因素调节NK细胞在不同成熟状态下的各种效应功能。根据我实验室发表的和初步的工作，我们提出了一个总体假设，以在本提案中进行测试：Helios和其他Ikaros家族成员代表了一类新的调节因子，它们决定NK激活时NK效应物的不同功能。我描述了4个独立但相互关联的研究主题，旨在描述短期目标，外部因素（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/细胞因子的产生。主题1。定义由活化DC产生的外部因素对NK细胞迁移特性的影响。我们将测试被不同微生物激活的成熟DC产生不同的趋化因子来调节不同的NK细胞迁移反应的子假设。主题2。确定罕见肽等外在因素如何影响nk介导的免疫监视机制的结果。我们将测试NK细胞被一种假定的受体激活以识别非自我的、罕见的短肽的子假设。主题3。定义细胞内因子的贡献，如基因调控分子，Helios和其他Ikaros家族成员在塑造NK细胞活化的功能结果。我们将检验Ikaros家族成员个体表达水平调控不同效应NK细胞功能的子假设。主题4。探讨GM-CSF对NK细胞排斥及其他有效功能影响的分子机制。我们将检验GM-CSF通过JAK2-Stats信号诱导NK细胞化学排斥的子假设。长期目标是建立一个路线图，说明这些因子如何在确定的成熟或激活状态下调节NK发育和特定效应物的功能。研究项目的新颖性和所涉及的尖端技术将为HQP的培训创造丰富的环境。

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.