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===========================================

超出所提供的空间。我们的长期目标是了解先天免疫的效应细胞如何调节免疫反应。NK细胞在这种调节中发挥主要作用，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细胞可能主要分别参与维持非适应性免疫和调节适应性反应的发展。我们已经确定，未成熟的CD 161 + CD 56- NK细胞对白细胞介素（IL）-4具有最高的增殖潜力，不能介导颗粒胞吐依赖性细胞毒性，并产生主要影响骨髓和B细胞的细胞因子[即肿瘤坏死因子（TNF）-α、粒细胞-巨噬细胞集落刺激因子（GM-CSF）和2型细胞因子白细胞介素（IL）-5和IL-13]。存在于外周的这些细胞发育，通过IL-13+干扰素（IFN）-阶段过渡为终末分化的表型成熟的CD 56+细胞，其发挥颗粒胞吐作用和Fas-配体（L）介导的细胞毒性，具有降低的产生TNF-α和GM-CSF的能力，是IL-13-，并且在它们经历凋亡性细胞死亡时仅产生IFN-γ，并且最终产生IL-10。这为我们的工作假设提供了基础，即外周NK细胞功能的定性调节主要通过任何因素调节未成熟外周NK细胞的末端线性发育来实现（细胞因子或细胞相互作用），通过诱导它们的增殖依赖性积累来延缓它，或通过诱导细胞对IL-12和其他尚未确定的诱导分化的刺激做出反应的变化来加速分化。我们的额外观察结果是，这种发育过程与T细胞共享，这使我们预测相同的细胞因子可以调节T细胞和NK细胞，并且NK细胞中参与靶细胞识别的一种或多种受体可以与TCR共享配体识别以外的功能。该工作假设将在3个特定目的中进行检验：1）确定IFN和其他选定细胞因子在终末NK细胞发育中的作用; 2）定义NK细胞上“活化”受体的调节和功能（细胞毒性除外）; 3）分析NK细胞来源于常见（2型细胞因子+）外周T/NK细胞祖细胞的可能性。这些研究的结果预计将为合理操纵先天系统提供基础，用于基于精氨酸的和/或免疫和预防性干预（例如接种病毒和肿瘤等病原体）。此外，定义存在于任何个体中的未成熟外周细胞如何可以维持和/或诱导分化为功能成熟的淋巴细胞与先天免疫的遗传操作及其在许多临床环境中的重建的可能性有关。性能现场=