Molecular and Cellular Regulation of Lymphocyte Exit by Interferon

干扰素对淋巴细胞退出的分子和细胞调节

• 批准号: 7179390
• 负责人: MEHRDAD MATLOUBIAN
• 金额: $ 11.59万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7179390
• 关键词: Molecular; Cellular; Regulation; Lymphocyte; Exit

DESCRIPTION (provided by applicant): Proper functioning of the immune system, in detecting and mounting an immune response against invading pathogens, is dependent on lymphocyte recirculation through secondary lymphoid organs. Lymphocyte entry and exit into these lymphoid tissues is a tightly regulated process. Disruption of this process can lead to sequestration of lymphocytes in lymphoid organs, as seen in infection with human immunodeficiency virus, and may contribute to immunosuppression of the host. A variety of cytokines, including interferon-a/¿ (IFN- a/¿ are known to transiently block lymphocyte egress. Since an increasing number of cytokines, including IFN-a/b are used as therapeutic agents, it is essential to understand the molecular mechanisms by which they affect lymphocyte trafficking. We have found that treatment of mice with the IFN-a/¿ inducer, polyinosine-polycytosine (PIC), inhibited egress through both lymphocyte intrinsic and extrinsic mechanisms. Lymphocyte egress is dependent on sphingosine-1 -phosphate receptor-1 (S1P1), and IFN-a/b was found to inhibit lymphocyte responsiveness to its ligand, sphingosine-1-phosphate (S1P). Loss of lymphocyte responsiveness to S1P was mediated by the transmembrane C-type lectin, CD69. In co-expression studies, CD69 co-immunoprecipitated with S1P1. Furthermore, CD69 inhibited S1P1 chemotactic function and led to S1P1 down-modulation. This is the first demonstration of negative regulation of a G-protein coupled receptor by a type II transmembrane glycoprotein. The goal of this application is to further understand the effects of IFN-a/¿ on lymphocyte egress with emphasis on the molecular basis of regulation of S1P1 by CD69. Cellular and biochemical approaches will be utilized to define (1) the mechanism of lymphocyte extrinsic effects of IFN-a/b on exit; (2) molecular requirements for S1P-I-CD69 interaction; (3) the fate of the molecular complex; and (4) effects on signaling pathways downstream of S1P1 . The candidate is a physician-scientist who is proposing a 3-year mentored research experience with Dr. Arthur Weiss at the University of California, San Francisco. The proposed training program is designed with the goal of preparing the applicant to establish an independent laboratory in an academic department.

描述（由申请人提供）： 免疫系统在检测和发起针对入侵病原体的免疫反应方面的正常功能取决于淋巴细胞通过次级淋巴器官的再循环。淋巴细胞进入和退出这些淋巴组织是一个严格调节的过程。这一过程的进行会导致淋巴器官中淋巴细胞的隔离，如人类免疫缺陷病毒感染中所见，并可能导致宿主的免疫抑制。包括干扰素-a/¿ （已知 IFN-a/¿ 会暂时阻止淋巴细胞流出。由于越来越多的细胞因子（包括 IFN-a/b）被用作治疗剂，因此有必要了解它们影响淋巴细胞运输的分子机制。我们已经发现用 IFN-a/¿ 诱导剂聚肌苷-多胞嘧啶 (PIC) 治疗小鼠，通过淋巴细胞内在和外在机制抑制淋巴细胞的排出。 1-磷酸鞘氨醇受体-1 (S1P1) 和 IFN-a/b 被发现可抑制淋巴细胞对其配体 1-磷酸鞘氨醇 (S1P) 的反应。淋巴细胞对 S1P 反应性的丧失是由跨膜 C- 介导的。型凝集素，CD69 在共表达研究中，CD69 与 S1P1 共免疫沉淀。 S1P1 趋化功能并导致 S1P1 下调。这是 II 型跨膜糖蛋白对 G 蛋白偶联受体负调节的首次证明。本应用的目的是进一步了解 IFN-a/¿ 的作用。单核细胞淋巴出口，重点是 CD69 调节 S1P1 的分子基础。将利用细胞和生化方法来定义 (1) IFN-a/b 对出口的淋巴细胞外在影响的机制；(2) S1P 的分子要求。 -I-CD69 相互作用；(3) 分子复合物的命运；以及 (4) 对 S1P1 下游信号通路的影响。在旧金山加利福尼亚大学 Arthur Weiss 博士指导下获得 3 年指导研究经验 拟议的培训计划旨在帮助申请人做好在学术部门建立独立实验室的准备。