ACTIVATION OF NON-MHC-RESTRICTED CYTOTOXIC LYMPHOCYTES

非 MHC 限制性细胞毒性淋巴细胞的激活

• 批准号: 2091818
• 负责人: BICE PERUSSIA
• 金额: $ 25.96万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1999-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2091818
• 关键词: B lymphocyte; antireceptor antibody; basophils; biological signal transduction; cell differentiation; cytokine receptors; dendritic cells; human tissue; in situ hybridization; interleukin 2; laboratory mouse; leukocyte activation /transformation; lymphokines; monocyte; natural killer cells; polymerase chain reaction; protein tyrosine kinase; receptor expression; tissue /cell culture

Natural Killer (NK) cells represent the major lymphocyte subset whose functions are elicited, in the initial phases of the host response to a variety of pathogens, and that are capable of cytotoxicity in an MHC- non-restricted fashion. Through production of cytokines, NK cells exert a regulatory role on other cell types and, on the other hand, their own biological functions are regulated by cytokines produced by other mononuclear cell subsets and, possibly, by themselves. Among the known cytokines, only IL-2 and IL-12 have been demonstrated capable of modulating proliferation of these cells directly. We have identified and characterized the biological functions exerted by IL-12 on NK cells and T lymphocytes. IL-12 is a novel cytokine that acts independently from IL-2 to induce activation and proliferation of prestimulated NK and T cells. It enhances spontaneous cytotoxicity of NK cells, induces cytokine production by PBL acting in synergy with IL-2 and a series of other stimuli, variably modulates proliferation of lymphocytes, and affects Th1 cells differentiation. Our data support the contention that the mechanisms by which the two cytokines affect NK and T cell functions are distinct, and likely do depend on induction of different intracellular activation pathways, although in both cases activation of tyrosine kinases may play a major functional role. Understanding the immunobiology of NK cells depends on defining the type of interactions that are elicited to induce production of cytokines and the binding of these to their specific receptors at the surface of the effector cells. In order to start dissecting these conditions we propose: 1) to identify the cell types that are involved in the production of IL-12, with particular attention to mononuclear cell subsets present in minor proportion among lymphocytes (e.g. B lymphocytes and their subsets, basophils, and monocytes), using a combination of cell separation, biochemical and molecular biology techniques; 2) to biochemically and functionally characterize the receptor(s) for this cytokine, focusing on understanding the basis for the receptor-mediated signal-transduction and induced tyrosine kinase activity; and 3) to determine whether IL-12 also acts as a differentiation factor for more immature NK cell populations, utilizing the culture system in which we have demonstrated preferential proliferation of mature NK cells. From the proposed studies we expect to derive relevant information to the immunobiology of NK cells, and of cytokines that enhance the functions of this and other cytotoxic cell types and are, at present considered for possible immunotherapeutic use in several pathological situations.

天然杀手（NK）细胞代表主要的淋巴细胞子集 在主机对A的初始响应的初始阶段引起了功能 多种病原体，并且能够在MHC-中具有细胞毒性 非限制的时尚。 通过生产细胞因子，NK细胞发挥 对其他细胞类型的调节作用，另一方面是他们自己的 生物学功能受到其他细胞因子的调节 单核细胞子集以及可能自己。 在已知的中 细胞因子，仅证明了IL-2和IL-12的能力 直接调节这些细胞的增殖。 我们已经确定了 并表征了IL-12在NK细胞上施加的生物学功能 和T淋巴细胞。 IL-12是一种独立起作用的新颖的细胞因子 从IL-2到诱导NK的激活和增殖 T细胞。 它增强了NK细胞的自发性细胞毒性，诱导 PBL与IL-2协同作用的细胞因子产生和一系列 其他刺激可变可调节淋巴细胞的增殖和 影响Th1细胞分化。 我们的数据支持以下论点 两种细胞因子影响NK和T细胞功能的机制 是不同的，很可能确实取决于不同的归纳 细胞内激活途径，尽管在两种情况下都激活 酪氨酸激酶可能起着主要的功能作用。 了解 NK细胞的免疫生物学取决于定义相互作用的类型 引起诱导细胞因子的产生和结合 这些是在效应细胞表面的特定受体。 为了开始剖析这些条件：1）确定 IL-12的生产中涉及的细胞类型， 特别注意次要中存在的单核细胞子集 淋巴细胞之间的比例（例如B淋巴细胞及其亚群， 嗜碱性粒细胞和单核细胞），结合细胞分离， 生化和分子生物学技术； 2）从生化和 在功能上表征该细胞因子的受体，重点 了解受体介导的信号转导的基础 并诱导酪氨酸激酶活性； 3）确定IL-12是否 也充当了更未成熟的NK细胞的分化因子 人口，利用我们证明的文化系统 成熟NK细胞的优先增殖。 从提议的 我们期望将相关信息得出的研究 NK细胞以及增强该功能和其他功能的细胞因子 细胞毒性细胞类型，目前已考虑 在几种病理情况下的免疫治疗用途。