Activation of Innate Immunity Effector Cells

我们的长期目标是了解免疫反应的发展是如何被免疫细胞的效应细胞调节的。 先天免疫NK细胞在这种调节中起主要作用，我们的初步数据表明， 生理作用取决于它们的发育阶段，不成熟和成熟的NK细胞可能 主要涉及，分别在维持非适应性免疫，并在调节的发展， 适应性反应我们已经确定，未成熟的CD 161 + CD 56- NK细胞具有最高的增殖能力， 对白细胞介素（IL）-4应答的潜力，不能介导颗粒胞吐依赖性细胞毒性， 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-β， 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]。 这些细胞存在于外周，通过IL-13+干扰素（IFN）-_阶段过渡，发展成 发挥颗粒胞吐作用和Fas配体的终末分化、表型成熟的CD 56+细胞 （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-，并且产生 仅仅是IFN-γ，最后是IL-10，因为它们经历凋亡性细胞死亡。这为我们的 工作假设，外周NK细胞功能的定性调节主要通过 通过任何因子（细胞因子或细胞毒性因子）调节未成熟外周NK细胞的末端线性发育， 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 诱导允许细胞响应IL-12和其他尚未定义的分化诱导的变化， 刺激。我们的额外观察表明，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，并且一种或多种受体参与调节T细胞和NK细胞。 NK细胞中的靶细胞识别可以与TCR共享除配体识别之外的功能。这 工作假设将在3个特定目的中进行检验：1）确定IFN和其他选定的 终末NK细胞发育中的细胞因子; 2）定义调节和功能（细胞毒性除外） 3）分析NK细胞来源于一种共同的、具有“激活”功能的受体的可能性， (type 2细胞因子+）外周T/NK细胞祖细胞。这些研究的结果预计将提出 合理操纵先天系统用于基于精氨酸和/或免疫的基础， 预防性干预措施（如接种病毒和肿瘤等病原体疫苗）。此外，定义如何 存在于任何个体中的未成熟外周细胞可被维持和/或诱导分化， 功能成熟的淋巴细胞与先天免疫的遗传操作的可能性有关， 它在许多临床环境中的重建。

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.