Activation of Innate Immunity Effector Cells

超出所提供的空间。我们的长期目标是了解发育中的免疫反应是如何被先天免疫效应细胞调节的。NK细胞在这种调节中起主要作用，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细胞在响应白细胞介素(IL)-4时具有最高的增殖潜力，不能介导颗粒胞吐依赖性细胞毒性，并产生主要影响髓细胞和B细胞的细胞因子[即肿瘤坏死因子(TNF)-ct、粒细胞-巨噬细胞集落刺激因子（GM-CSF）和2型细胞因子白介素(IL)-5和IL-13]。这些细胞存在于外周，通过IL-13+干扰素(IFN)-_阶段，发展为终末分化，表型成熟的CD56 +细胞，发挥颗粒胞分泌和fas配体(L)介导的细胞毒性，产生TNF-o_和GM-CSF的能力下降，产生IL-13-，只产生IFN-y，最终产生IL-10，因为它们经历凋亡细胞死亡。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是通过调节未成熟外周NK细胞的终末线性发育来实现的，这些未成熟外周NK细胞通过诱导其增殖依赖性积累来延缓其发育，或通过诱导允许细胞对IL-12和其他尚未定义的分化诱导刺激作出反应的变化来加速其发育。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调节T细胞和NK细胞，并且NK细胞中参与靶细胞识别的一个或多个受体可能与TCR功能共享，而不是配体识别。这一工作假设将在3个具体目标中得到验证：1)确定IFN和其他选定的细胞因子在NK细胞晚期发育中的作用；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。这些研究的结果有望为基于细胞因子和/或免疫治疗和预防干预（例如对病毒和肿瘤等病原体接种疫苗）的先天系统的合理操作奠定基础。此外，定义存在于任何个体中的未成熟外周细胞如何被维持和/或诱导分化为功能成熟的淋巴细胞，与遗传操纵先天免疫及其在许多临床环境中的重建的可能性有关。网站性能 ======================================== 节结束 ===========================================

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