Activation of Innate Immunity Effector Cells

先天免疫效应细胞的激活

• 批准号: 6838210
• 负责人: BICE PERUSSIA
• 金额: $ 35.33万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6838210
• 关键词: Activation; Innate; Immunity; Effector; Cells

EXCEED THE SPACE PROVIDED. Our long term goal is to understand how developing immune responses are regulated by effector cells of innate immunity. NK cells play a primary role in this regulation, and our preliminary data suggest that their physiological role(s) depend on their developmental stage, with immature and mature NK cells likely primarily involved, respectively, in maintaining non-adaptive immunity, and in regulating the development of adaptive responses. We have defined that immature CD161+CD56 - NK cells have highest proliferative potential in response to interleukin (IL)-4, can not mediate granule exocytosis-dependent cytotoxicity and produce cytokines that primarily affect myeloid and B cells [i.e. tumor necrosis factor (TNF)-ct, Granulocyte- Macrophage Colony Stimulating Factor (GM-CSF), and the type 2 cytokines interleukin (IL)-5 and IL-13]. These cells, present in the periphery, develop, transiting through an IL-13+Interferon (IFN)-_ stage, into terminally differentiated, phenotypically mature CD56 + cells that exert granule exocytosis- and Fas-ligand (L)-mediated cytotoxicity, have decreased ability to produce TNF-o_ and GM-CSF, are IL-13-, and produce exclusively IFN-y, and finally IL-10 as they undergo apoptotic cell death. This poses the basis for our working hypothesis that qualitative modulation of peripheral NK cell functions is achieved primarily via modulation of the terminal linear development of the immature peripheral NK cells by any factor (cytokine or cellular interaction) that retards it by inducing their proliferation-dependent accumulation, or accelerates it by inducing changes that allow the cells to respond to IL-12 and other yet-to-be defined differentiation-inducing stimuli. Our additional observation that this developmental process is shared with T cells leads us to predict that the same cytokines may regulate it both T and NK cells, and that one or more receptor(s) involved in target cell recognition in NK cells may share with the TCR functions other than ligand recognition. This working hypothesis will be tested in 3 Specific Aims: 1) To determine the role of IFN and other selected cytokines in terminal NK cell development; 2) To define the regulation and function (other than cytotoxicity) of "activating" receptors on NK cells; 3) To analyze the possibility that NK cells derive from a common (type 2 cytokine +) peripheral T/NK cell progenitor cell. The results of these studies are expected to pose the bases for rational manipulation of the innate system for cytokine-based and/or immunotherapeutic and preventive interventions (e.g. vaccinations to pathogens like viruses and tumors). Also, defining how immature peripheral cells, present in any individual, can be maintained and/or induced to differentiate to functionally mature lymphocytes is relevant to the possibility of genetic manipulation of innate immunity and its reconstitution in numerous clinical settings. PERFORMANCE SITE ========================================Section End===========================================

超过提供的空间。我们的长期目标是了解开发免疫反应如何受到先天免疫的效应细胞的调节。 NK细胞在该调节中起主要作用，我们的初步数据表明它们的生理作用取决于它们的发育阶段，未成熟和成熟的NK细胞可能分别主要参与维持非自适应免疫性，并在调节适应性反应的发展中。我们已经确定，未成熟的CD161+CD56-NK细胞在响应白介素（IL）-4的响应中具有最高的增殖潜力，无法介导颗粒胞吐依赖性细胞毒性，并产生主要影响髓样和B细胞的细胞因子[即。肿瘤坏死因子（TNF）-CT，粒细胞 - 巨噬细胞刺激因子（GM-CSF）以及2型细胞因子白介素（IL）-5和IL-13]。 These cells, present in the periphery, develop, transiting through an IL-13+Interferon (IFN)-_ stage, into terminally differentiated, phenotypically mature CD56 + cells that exert granule exocytosis- and Fas-ligand (L)-mediated cytotoxicity, have decreased ability to produce TNF-o_ and GM-CSF, are IL-13-, and produce exclusively IFN-y, and最后，IL-10在发生凋亡细胞死亡时。这为我们的工作假设奠定了基础，即外围NK细胞功能的定性调节主要是通过通过任何因素（细胞因子或细胞相互作用）（细胞因子或细胞相互作用）来调节未成熟外周外围NK细胞的终末线性发育来实现的，从而通过其诱导其依赖于增殖的细胞来诱导其依赖的细胞和加速响应的任何因素（细胞因子或细胞相互作用）来诱导其疾病，或者允许其变化。12诱导刺激。我们对这种发育过程与T细胞共享的其他观察结果使我们预测相同的细胞因子可以调节其T和NK细胞，并且在NK细胞中参与靶细胞识别的一个或多个受体可能与配体识别以外的TCR功能共享。该工作假设将在3个特定目的中进行测试：1）确定IFN和其他选定的细胞因子在末端NK细胞发育中的作用； 2）定义NK细胞上“激活”受体的调节和功能（除细胞毒性之外）； 3）分析NK细胞从常见（2型细胞因子 +）周围T/NK细胞祖细胞衍生而来的可能性。这些研究的结果有望为基于细胞因子和/或免疫治疗和预防性干预措施的先天系统合理操纵（例如，对病毒和肿瘤等病原体的疫苗接种）构成基础。同样，定义任何个体中存在的不成熟的外围细胞如何保持和/或诱导以区分功能成熟的淋巴细胞与在众多临床环境中对先天免疫及其重新建立的基因操纵的可能性有关。表演站点=============================================================================================