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.

自然杀伤（NK）细胞代表主要的淋巴细胞亚群， 在宿主响应的初始阶段， 各种病原体，并且能够在MHC中具有细胞毒性- 不受限制的时尚 通过产生细胞因子，NK细胞发挥 对其他细胞类型的调节作用，另一方面， 生物学功能由其他细胞产生的细胞因子调节。 单核细胞亚群，可能是它们自己。 在已知的 细胞因子，只有IL-2和IL-12已被证明能够 直接调节这些细胞的增殖。 我们已经确定 并表征了IL-12对NK细胞的生物学功能 和T淋巴细胞。 IL-12是一种新的细胞因子， 从IL-2诱导预刺激的NK的活化和增殖， T细胞。 它增强NK细胞的自发细胞毒性，诱导 PBL与IL-2协同作用产生的细胞因子以及一系列的 其他刺激物可调节淋巴细胞的增殖， 影响Th 1细胞的分化。 我们的数据支持这样的论点， 两种细胞因子影响NK和T细胞功能的机制 是不同的，很可能取决于不同的诱导， 细胞内激活途径，虽然在这两种情况下， 酪氨酸激酶可能起主要的功能作用。 了解 NK细胞的免疫生物学依赖于确定相互作用的类型 其被引发以诱导细胞因子的产生和细胞因子的结合。 它们与效应细胞表面的特异性受体结合。 为了开始解剖这些条件，我们建议：1）识别 参与IL-12产生的细胞类型， 特别注意单核细胞亚群， 淋巴细胞（例如B淋巴细胞及其亚群， 嗜碱性粒细胞和单核细胞），使用细胞分离的组合， 生物化学和分子生物学技术; 2）生物化学和 功能上表征该细胞因子的受体，重点是 了解受体介导的信号转导的基础 和诱导的酪氨酸激酶活性;和3）确定IL-12是否 也作为一个分化因子为更不成熟的NK细胞 利用我们已经证明的文化系统， 成熟NK细胞的优先增殖。 从拟议 我们希望通过这些研究获得与免疫生物学相关的信息， NK细胞，以及增强这种和其他细胞功能的细胞因子。 细胞毒性细胞类型，目前被认为是可能的 在几种病理情况下使用免疫抑制剂。