ACTIVATION OF NON-MHC-RESTRICTED CYTOTOXIC LYMPHOCYTES

自然杀伤(NK)细胞代表其主要淋巴细胞亚群 函数是在宿主对 各种病原体，并且能够在MHC中产生细胞毒性- 不受限制的时尚。通过产生细胞因子，NK细胞发挥作用 对其他细胞类型的调节作用，另一方面，对它们自己的调节作用 生物功能由其他细胞产生的细胞因子调节 单核细胞亚群和，可能是它们自己。在已知的人中 细胞因子，只有IL-2和IL-12被证明能够 直接调节这些细胞的增殖。我们已经确定了 并表征了IL-12对NK细胞的生物学功能 和T淋巴细胞。IL-12是一种新的独立发挥作用的细胞因子 IL-2诱导预刺激的NK细胞活化和增殖 T细胞。它能增强自然杀伤细胞的自发杀伤活性，诱导 PBL与IL-2及一系列细胞因子协同作用产生细胞因子 其他刺激，可变地调节淋巴细胞的增殖，以及 影响Th1细胞分化。我们的数据支持这样一种观点 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诱导 细胞内激活途径，尽管在这两种情况下激活 酪氨酸激酶可能起着重要的功能作用。了解 NK细胞的免疫生物学依赖于确定相互作用的类型 以诱导细胞因子的产生和结合 它们与效应器细胞表面的特定受体结合。 为了开始剖析这些条件，我们建议：1)确定 参与IL-12产生的细胞类型， 对未成年人中存在的单个核细胞亚群的特别关注 淋巴细胞的比例(例如B淋巴细胞及其亚群， 嗜碱性粒细胞和单核细胞)，使用细胞分离的组合， 生化和分子生物学技术；2)生物化学和 从功能上表征这种细胞因子的受体(S)，重点是 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 也是更多未成熟NK细胞的分化因子 人口，利用我们已经展示的文化系统 成熟NK细胞优先增殖。从建议的 我们希望从这些研究中获得与免疫生物学相关的信息 NK细胞，以及增强这个和其他细胞功能的细胞因子 细胞毒性细胞类型，目前被认为可能 免疫治疗在几种病理情况下的应用。

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.