Activation of Innate Immunity Effector Cells

描述(申请人提供)：我们的长期目标是了解先天免疫的效应细胞是如何调节发育中的免疫反应的。NK细胞在这一调节中起主要作用，我们的初步数据表明，它们的生理作用(S)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获得性免疫和调节适应性反应的发展。我们认为未成熟的CD161+CD56-NK细胞对IL-4的反应具有最高的增殖能力，不能介导颗粒吐出依赖的细胞毒作用，并产生主要影响髓系细胞和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-IL-5和IL-13]。这些细胞存在于外周，发育并过渡到IL-13+干扰素-γ+阶段，进入终末分化的成熟CD56+细胞，发挥颗粒吐出和Fas-配体(L)介导的细胞毒作用，产生肿瘤坏死因子-α和GM-CSF的能力降低，IL-13-，并仅产生干扰素-γ，最后在细胞凋亡时产生IL-10。这为我们的工作假设奠定了基础，即外周NK细胞功能的质的调节主要是通过任何因素(细胞因子或细胞相互作用)调节未成熟的外周NK细胞的末端线性发育来实现的，这些因素通过诱导依赖于增殖的积累来抑制它，或者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做出反应的变化来加速它。我们进一步观察到，这种发育过程与T细胞相同，这使我们预测，同样的细胞因子可能对T细胞和NK细胞都有调节作用，参与NK细胞靶细胞识别的一个或多个受体(S)可能与T细胞受体具有配体识别以外的其他功能。这一工作假说将在3个具体目标中得到验证：1)确定干扰素和其他选定的细胞因子在NK细胞终末发育中的作用；2)确定NK细胞上“激活”受体的调节和功能(除细胞毒性外)；3)分析NK细胞来自共同的(2型细胞因子+)外周T/NK细胞前体细胞的可能性。这些研究的结果有望为合理操纵基于细胞因子的和/或免疫治疗和预防干预(例如，对病毒和肿瘤等病原体的疫苗)的先天系统奠定基础。此外，确定存在于任何个体中的未成熟外周细胞如何维持和/或诱导分化为功能成熟的淋巴细胞，与在许多临床环境中对先天免疫及其重建的遗传操作的可能性有关。

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.