Activation of Innate Immunity Effector Cells

先天免疫效应细胞的激活

• 批准号: 6670532
• 负责人: BICE PERUSSIA
• 金额: $ 17.66万
• 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/6670532
• 关键词: T cell receptor; cell differentiation; clinical research; developmental immunology; hematopoietic stem cells; human subject; immunologic receptors; interferons; leukocyte activation /transformation; lymphocyte proliferation; natural killer cells; receptor expression

DESCRIPTION (provided by applicant): 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)-alpha, 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)-gamma+ stage, into terminally differentiated, phenotypically mature CD56+ cells that exert granule exocytosis- and Fas-ligand (L)-mediated cytotoxicity, have decreased ability to produce TNF-alpha and GM-CSF, are IL-13-, and produce exclusively IFN-gamma, 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.

描述（由申请人提供）：我们的长期目标是了解先天免疫的效应细胞如何调节正在发展的免疫反应。 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其发育阶段，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 CD161+CD56-NK 细胞响应白细胞介素 (IL)-4 具有最高的增殖潜力，不能介导颗粒胞吐作用依赖性细胞毒性，并产生主要影响骨髓细胞和 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]。这些存在于外周的细胞，通过 IL-13+ 干扰素 (IFN)-gamma+ 阶段发育，转变为终末分化、表型成熟的 CD56+ 细胞，这些细胞发挥颗粒胞吐作用和 Fas 配体 (L) 介导的细胞毒性，产生 TNF-α 和 GM-CSF 的能力下降，为 IL-13-，并且专门产生 IFN-γ，最后是 IL-10，因为它们经历细胞凋亡。这为我们的工作假设奠定了基础，即外周 NK 细胞功能的定性调节主要是通过任何因素（细胞因子或细胞相互作用）调节未成熟外周 NK 细胞的终末线性发育来实现的，这些因素通过诱导其增殖依赖性积累来延缓其发展，或通过诱导允许细胞对 IL-12 和其他尚未定义的物质作出反应的变化来加速其发展。 分化诱导刺激。我们进一步观察到这一发育过程与 T 细胞共享，这使我们预测相同的细胞因子可能会调节 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能与配体识别以外的 TCR 功能共享。这一工作假设将在 3 个具体目标中得到检验： 1) 确定 IFN 和其他选定的细胞因子在终末 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（细胞毒性除外）； 3) 分析NK细胞来源于共同的（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以进行基于细胞因子和/或免疫治疗和预防干预（例如针对病毒和肿瘤等病原体的疫苗接种）奠定基础。此外，定义如何维持和/或诱导任何个体中存在的未成熟外周细胞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重建的可能性相关。