Activation of Human Natural Killer Cell Function

人类自然杀伤细胞功能的激活

• 批准号: 8745307
• 负责人: Eric O Long
• 金额: $ 37.24万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 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/8745307
• 关键词: Adhesions; Antigens; B-Lymphocytes; Binding; Cell Degranulation; Cell Line; Cell Proliferation; Cell Survival; Cell physiology; Cells; Communicable Diseases; Complex; Cytoplasmic Granules; Drosophila genus; Elements; Equilibrium; Genes; Genetic Transcription; Goals; Hematopoietic Neoplasms; Human; Individual; Inflammation; Insecta; Integrins; Interleukin-15; Leukocytes; Ligands; Maintenance; NK Cell Activation; Natural Killer Cells; Normal Cell; Receptor Activation; Receptor Signaling; Regulation; Resistance; Signal Transduction; System; T-Lymphocyte; cancer immunotherapy; cell killing; cytokine; cytotoxicity; functional outcomes; immunological synapse; interleukin-15 receptor; neoplastic cell; pathogen; receptor; reconstitution; response

After completion of several of our objectives in FY12, this project has taken a new direction. We are defining the minimal requirements for the activation of NK cell proliferation, using approaches that have been successful in previous projects. The interleukin 15 (IL-15) is essential for NK cell survival and proliferation. Unlike other cytokines, which are soluble, IL-15 is bound to the alpha chain of the IL-15 receptor (IL-15R). The IL-15Ralpha-IL-15 complex is not expressed on NK cells but on other cells, which trans-present IL-15 to the beta and gamma chains of the IL-15R expressed on NK cells. The IL-15Rbetagamma complex then transmits signals to the NK cell for survival, proliferation, and transcription of a specific set of genes. Trans-presentation of IL-15 in the context of an immunological synapse opens the possibility that signaling for NK cell proliferation may be subject to regulation by other receptor-ligand interactions. Using insect cells transfected with IL-15Ralpha, either alone or in combination with ligands for other NK receptors, we have shown that IL-15 trans-presentation occurs independently of adhesion through integrin, and of signaling by other activation receptors.

在2012财年完成了我们的几个目标之后，该项目朝着新的方向发展。我们使用先前项目成功的方法来定义NK细胞增殖激活的最小要求。白介素15（IL-15）对于NK细胞的存活和增殖至关重要。与其他可溶性细胞因子不同，IL-15与IL-15受体（IL-15R）的α链结合。 IL-15ralpha-IL-15复合物不是在NK细胞上，而是在其他细胞上表达的，这些复合物是在NK细胞上表达的IL-15R的β和伽马链的其他细胞上表达的。然后，IL-15rbetagamma复合物将信号传输到NK细胞，以使一组特定基因的生存，增殖和转录。在免疫突触的背景下，IL-15的反式呈递打开了NK细胞增殖的信号传导可能会受到其他受体配体相互作用的调节。使用用IL-15ralpha转染的昆虫细胞，单独或与其他NK受体的配体结合使用，我们已经表明，IL-15反式出现是独立于通过整合素和其他激活受体信号传导的独立于粘附的。