ACTIVATION AND TRIGGERING OF CYTOXIC CELLS

细胞毒性细胞的激活和触发

• 批准号: 6161049
• 负责人: D M SEGAL
• 金额: --
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 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/6161049
• 关键词: CD16 molecule; CD44 molecule; T lymphocyte; antitumor antibody; biological signal transduction; breast neoplasms; cell adhesion molecules; cell mediated cytotoxicity; cytolysis; interleukin 2; laboratory mouse; leukocyte activation /transformation; natural killer cells; neoplasm /cancer immunology; neoplastic growth; protein tyrosine kinase

We have previously used redirected cytotoxicity experiments to study and define triggering molecules on cytotoxic cells. While the TcR and FcR are the principal triggering molecules on human leukocytes, we have recently found that adhesion molecules can also serve as cytotoxic triggers on some cell types. In this project we have used redirected lysis to identify several cytotoxic triggering molecules on human NK cells. We show that upon activation with IL-2, CD38, CD44, CD56, and CD69 acquire triggering function in NK cells but not in CTL. By contrast, MHC-1, B2 integrins, and NKR-P1A failed to trigger lysis. Effector:target conjugates were induced by mAbs to both triggering and non-triggering receptors, indicating that conjugate formation per se was not a lytic signal. Actinomycin D blocked the induction of triggering capacity of CD38, CD44, CD56, and CD69, but failed to abolish FcRIIIA- mediated lysis or the surface expression of CD38, CD44 and CD69. We suggest that IL-2 stimulates the de novo expression of proteins that serve as intermediaries between several NK surface receptors and the lytic machinery. Such linker proteins could control the target cell specificty of natural cytotoxicity. Effector cells gain cytotoxic capacity upon activation, but in a number of conditions the gain of killing function is suppressed. To investigate the basis of immunosuppression, lymphocytes were screened for abnormalities in the expression of signal transducing proteins known to be involved in the regulation of cellular immunity. Cells from immunosuppressed tumor bearing mice and from HIV infected patients were used in these experiments. In both cases, a selective loss in STAT5 protein expression was observed. Since STAT5 is an essential component in the signalling pathway of several cytokines that are required for immune function, it is possible that the downregulation of this transcription factor plays an important role in the observed suppression of immune function.

我们以前使用重定向细胞毒性实验来研究和 定义细胞毒性细胞上的触发分子。而TcR和FcR 是人类白细胞上的主要触发分子， 最近发现，粘附分子也可以作为细胞毒性， 会触发某些细胞类型在这个项目中，我们使用了重定向 裂解以鉴定人NK上的几种细胞毒性触发分子 细胞我们发现，在用IL-2激活后，CD 38、CD 44、CD 56和 CD 69在NK细胞中获得触发功能，但在CTL中不获得。通过 相反，MHC-1、B2整联蛋白和NKR-P1 A不能触发裂解。 效应物：靶缀合物由mAb诱导以触发和抑制靶缀合物。 非触发受体，表明缀合物形成本身是 而不是裂解信号放线菌素D阻断触发的诱导 CD 38，CD 44，CD 56和CD 69的能力，但未能消除FcRIIIA- 介导的裂解或CD 38、CD 44和CD 69的表面表达。我们 表明IL-2刺激蛋白质的从头表达， 作为几种NK表面受体和NK细胞之间的中介， 裂解机制这种连接蛋白可以控制靶细胞 天然细胞毒性的特异性。 效应细胞在激活后获得细胞毒性能力，但在一些情况下， 条件的抑制作用的增益。探讨 在免疫抑制的基础上，筛选淋巴细胞， 已知的信号转导蛋白的表达异常， 参与细胞免疫的调节。细胞 免疫抑制的荷瘤小鼠和来自HIV感染患者的肿瘤细胞， 在这些实验中使用。在这两种情况下，STAT 5的选择性缺失 观察蛋白表达。由于STAT 5是一个重要的组成部分， 在几种细胞因子的信号通路中， 免疫功能，这是可能的下调， 转录因子在观察到的抑制中起重要作用 免疫功能。