ACTIVATION AND TRIGGERING OF CYTOXIC CELLS

细胞毒性细胞的激活和触发

• 批准号: 6100949
• 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/6100949
• 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