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: 7430279
• 负责人: MEHRDAD MATLOUBIAN
• 金额: $ 0.96万
• 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 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7430279
• 关键词: Acquired Immunodeficiency Syndrome; Affect; Biochemical; Bone Marrow; C-Type Lectins; California; Cells; Chimera organism; Chimeric Proteins; Complex; Disruption; Facility Construction Funding Category; G-Protein-Coupled Receptors; Generations; Glycoproteins; Goals; HIV; Hepatitis C; Immune response; Immune system; Immunologic Surveillance; Immunosuppression; Infection; Interferons; Invaded; Laboratories; Lead; Ligand Binding; Ligands; Lupus; Lymphocyte; Lymphoid; Lymphoid Tissue; Lymphopenia; Mediating; Mediator of activation protein; Mentors; Metabolism; Molecular; Molecular Target; Multiple Sclerosis; Mus; Numbers; Organ; Pathologic Processes; Patients; Physicians; Post-Translational Protein Processing; Process; Recombinants; Regulation; Research; Role; San Francisco; Scientist; Signal Pathway; Site; Sphingosine-1-Phosphate Receptor; Therapeutic Agents; Therapeutic immunosuppression; Training Programs; Tumor Necrosis Factor-alpha; Universities; base; cell growth regulation; cytokine; design; experience; lymph nodes; pathogen; sphingosine 1-phosphate; trafficking

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（由适用提供）：在检测和安装针对入侵病原体的免疫响应时，免疫系统的适当功能取决于通过继发性淋巴机器人的淋巴细胞再循环。淋巴细胞进入并进入这些淋巴组织是一个严格调节的过程。这种过程的破坏会导致淋巴器官中的淋巴细胞疗程，如人类免疫缺陷病毒感染所见，并可能有助于宿主的免疫抑制。多种细胞因子，包括干扰素A/¿多美去细胞胞菌素（PIC）通过淋巴细胞的固有和外部机制抑制出口淋巴细胞对S1P的反应是由CD69介导的，CD69在CD69中与S1P1共征收。跨膜糖蛋白。该应用的目的是进一步了解IFN-A/¿对淋巴细胞出口的影响，重点是CD69调节S1P1的分子基础。细胞和生化方法将用于定义（1）IFN-A/B对出口的淋巴细胞外部作用的机理； （2）S1P-I-CD69相互作用的分子需求； （3）分子络合物的命运； （4）对S1P1下游信号通路的影响。候选人是一名身体科学家，他在加利福尼亚大学旧金山分校的Arthur Weiss博士提出了为期3年的指导研究经验。拟议的培训计划的设计目的是准备在学术部门建立独立实验室的应用程序。