Regulation Of Natural Killer Cell Activity

自然杀伤细胞活性的调节

• 批准号: 6669749
• 负责人: Eric O Long
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6669749
• 关键词: cell mediated cytotoxicity; genetically modified animals; human tissue; immunoregulation; laboratory mouse; leukocyte activation /transformation; mast cell; natural killer cells; receptor; receptor expression

Natural killer (NK) cells are a third subtype of lymphocytes besides B and T cells. NK cells provide an important immune function in the defense against viruses and other intracellular pathogens. Unlike B and T cells, NK cells do not exhibit specificity for antigen and they acquired their name because they can kill cells without prior stimulation by antigen. The killing of normal healthy cells is prevented by inhibitory receptors on NK cells that recognize major histocompatibility class I molecules. A large number of receptors that activate the cytotoxic response of NK cells have been described. However, it is not clear if any one of these receptors is sufficient and/or necessary to activate natural cytotoxicity. The major goal of this project is to define the molecular basis of NK cell activation and to characterize the receptors involved. A reconstitution system has been developed to test for the contribution of individual receptors to the activation of NK cell cytotoxicity. Several specific ligands of NK cell receptors were expressed in an insect cell line in order to define the requirements for activation of NK cell cytotoxicity. Surprisingly, expression of ICAM-1 alone was sufficient to induce lysis of the insect cells, suggesting that the integrin LFA-1 is essential not only for adhesion of NK cells to target cells, but also for transmitting activation signals. Expression of ligands for other NK cell activation receptors (such as CD16, CD2, and 2B4) was not sufficient to induce cytotoxicity but co-expression with ICAM-1 did enhance the lysis induced by ICAM-1 alone. The regulation of effector functions in resting NK cells is not well understood. The insect cell system was used to show that engagement of receptors CD2 and 2B4 by their respective ligand on target cells resulted in a strong enhancement of adhesion, even in the absence of cytokines or chemokines. The NK cell receptor KIR2DL4 has the unique property of inducing interferon-gamma production, but not cytotoxicity, by resting NK cells in the absence of cytokines. A DNA microarray study, followed by protein analysis, revealed that KIR2DL4 ligation induces a pro-inflammatory response. Furthermore, KIR2DL4 carries an unusual combination of structural elements that endow it with both activating and inhibitory potential.

自然杀伤（NK）细胞是B和T细胞以外的淋巴细胞的第三个亚型。 NK细胞在防御病毒和其他细胞内病原体的防御方面具有重要的免疫功能。与B和T细胞不同，NK细胞对抗原没有表现出特异性，并且获得了其名称，因为它们可以杀死细胞而无需先前抗原刺激。识别主要组织相容性I类分子的NK细胞上的抑制受体可以预防正常健康细胞的杀戮。已经描述了大量激活NK细胞细胞毒性反应的受体。但是，尚不清楚这些受体中的任何一个是否足够和/或激活自然细胞毒性。该项目的主要目标是定义NK细胞激活的分子基础并表征所涉及的受体。已经开发了一个重构系统来检验单个受体对NK细胞细胞毒性激活的贡献。 NK细胞受体的几种特定配体在昆虫细胞系中表达，以定义激活NK细胞细胞毒性的要求。令人惊讶的是，仅ICAM-1的表达足以诱导昆虫细胞的裂解，这表明整联蛋白LFA-1不仅对于NK细胞对靶细胞的粘附至关重要，而且对于传输激活信号也是必不可少的。其他NK细胞活化受体（例如CD16，CD2和2B4）的配体的表达不足以诱导细胞毒性，但与ICAM-1共表达确实可以增强ICAM-1单独引起的裂解。对静止NK细胞中效应子功能的调节尚不清楚。使用昆虫细胞系统表明受体CD2和2B4在靶细胞上通过其各自的配体参与，即使在没有细胞因子或趋化因子或趋化因子的情况下，也会导致粘附的强烈增强。 NK细胞受体KIR2DL4具有在没有细胞因子的情况下静止NK细胞，具有诱导干扰素γ的独特特性，而不是细胞毒性。 DNA微阵列研究，然后进行蛋白质分析，发现KIR2DL4连接诱导了促炎反应。此外，KIR2DL4具有赋予其激活和抑制潜力的结构元素的异常组合。