ACTIVATION AND TRIGGERING OF CYTOXIC CELLS

我们以前曾使用重定向细胞毒性实验来研究和 定义细胞毒细胞上的触发分子。而TCR和FCR 是人类白细胞上的主要触发分子，我们有 最近发现，黏附分子也可以起到细胞毒的作用 在某些细胞类型上触发。在本项目中，我们使用了重定向 裂解法鉴定几种人NK细胞毒触发分子 细胞。我们发现，在IL-2、CD38、CD44、CD56和 CD69在NK细胞中具有触发功能，但在CTL中不具有触发功能。通过 相比之下，MHC-1、B2整合素和NKR-P1a未能触发裂解。 效应器：mAbs可诱导靶向偶联物的触发和 非触发受体，表明偶联形成本身是 不是一个抒情的信号。放线菌素D阻断了触发的诱导 CD38、CD44、CD56和CD69的能力，但未能废除FcRIIIA- 介导CD38、CD44和CD69的裂解或表面表达。我们 提示IL-2刺激蛋白质从头开始表达 在多种NK细胞表面受体和细胞因子之间起中介作用 裂解机器。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能力，但数量很多 在某些条件下，杀伤函数的增益被抑制。去调查 在免疫抑制的基础上，对淋巴细胞进行筛选 已知的信号转导蛋白表达异常 参与细胞免疫的调节。单元格来自 免疫抑制的荷瘤小鼠和来自HIV感染患者的 在这些实验中使用。在这两种情况下，STAT5中的选择性损失 观察蛋白质的表达情况。因为STAT5是一个基本组件 在几种细胞因子的信号通路中，这些细胞因子是 免疫功能，有可能这种下调 转录因子在观察到的抑制中起着重要作用 对免疫功能的影响。

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.