Regulation of Lymphocyte Trafficking by S1P1 and CD69

S1P1 和 CD69 对淋巴细胞贩运的调节

• 批准号: 8080939
• 负责人: MEHRDAD MATLOUBIAN
• 金额: $ 30.29万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8080939
• 关键词: Acute; Affect; Antigen Receptors; Autoimmune Diseases; Autoimmune Process; Biochemical; Biological Models; Blood Circulation; C-Type Lectins; Chimeric Proteins; Chronic; Complex; Development; Disease; Down-Regulation; Event; G-Protein-Coupled Receptors; Generations; Genetic; Goals; HIV Infections; Health; Immune response; Immune system; Immunosuppression; Immunotherapy; Inflammation; Inflammatory; Interferon Type I; Interferon-alpha; Interferon-beta; Invaded; Knowledge; Lead; Leukocytes; Ligand Binding; Lymphocyte; Lymphoid; Lymphoid Tissue; Memory; Molecular; Mus; Organ; Phase; Phospholipids; Post-Translational Protein Processing; Process; Regulation; Research; Role; Signal Pathway; Sphingosine-1-Phosphate Receptor; Staging; Surface; System; T cell response; T-Lymphocyte; Transgenic Organisms; Viral; Virus; Virus Diseases; base; cytokine; improved; in vivo; mRNA Expression; microorganism; pathogen; programs; receptor; receptor function; therapeutic target; therapy development; trafficking; vaccine development

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. Factors that affect lymphocyte entry and exit into these lymphoid tissues are not completely understood. Furthermore, persistent pathological disruption of lymphocyte recirculation can lead to sequestration of lymphocytes in lymphoid organs, as seen in HIV infection, and may contribute to immunosuppression of the host. The long-term goal of our research program is to gain a detailed molecular understanding of regulation of lymphocyte trafficking in acute and chronic inflammation using viral infections as a model system. We have found that expression of a phospholipid receptor, sphingosine-1-phosphate receptor-1 (S1P1), within lymphocytes is required for their ability to exit from secondary lymphoid organs. Both innate and adaptive immune responses alter the expression and function of this receptor leading to lymphocyte sequestration. A variety of cytokines, including interferon alpha/beta (IFN), up-regulate expression of the transmembrane C-type lectin, CD69. CD69 interacts with and down-modulates surface expression and function of S1P1, a G protein coupled receptor, leading to transient lymphocyte sequestration. In addition, engagement of the antigen receptor on T cells leads to transcriptional down-regulation of S1P1 mRNA expression and a prolonged inhibition of lymphocyte egress. Thus, S1P1 function is tightly regulated by two distinct mechanisms during the early stages of an immune response. The goal of this proposal is to further understand the regulation of lymphocyte trafficking by S1P1 and CD69 and its impact on generation of T cell responses. Cellular and biochemical approaches will be utilized to determine: (1) the molecular requirements for S1P1-CD69 interaction; (2) the molecular mechanism of inhibition of S1P1 function by CD69; and (3) the effects of genetic perturbation of regulation of S1P1 expression and function on in vivo T cell responses to a viral infection. Our hope is that a detailed understanding of factors that regulate lymphocyte trafficking can contribute not only to vaccine development and improved immunotherapies, but also provide targets for therapeutic disruption of these processes in autoimmune and chronic inflammatory diseases. PUBLIC HEALTH RELEVENCE: Circulation of white blood cells through lymphoid tissues is essential for initiation of immune responses to infectious microorganisms such as viruses but could also have detrimental consequences in chronic inflammatory and autoimmune diseases. The goal of this proposal is to gain a detailed understanding of how two specific molecules known to affect white blood cell trafficking regulate this process. The knowledge gained from these studies will facilitate development of therapies that target white blood cell trafficking for treatment of inflammatory diseases.

描述（由申请人提供）：在检测和安装对入侵病原体的免疫反应时，免疫系统的正确功能取决于通过继发性淋巴机器人的淋巴细胞再循环。影响淋巴细胞进入并退出这些淋巴组织的因素尚不完全了解。此外，如在HIV感染中所见，淋巴细胞再循环的持续病理破坏会导致淋巴机构中淋巴细胞的隔离，并可能有助于宿主的免疫抑制。我们的研究计划的长期目标是通过使用病毒感染作为模型系统对急性和慢性炎症中淋巴细胞运输的调节进行详细的分子理解。我们已经发现，淋巴细胞内磷脂受体，鞘氨酸-1-磷酸受体1（S1P1）的表达对于它们从继发性淋巴机器人器官中退出的能力是必需的。先天和适应性免疫反应都会改变该受体的表达和功能，从而导致淋巴细胞隔离。各种细胞因子，包括干扰素α/β（IFN），上调跨膜C型凝集素的表达，CD69。 CD69与G蛋白偶联受体S1P1的表面表达和功能相互作用，从而导致瞬时淋巴细胞隔离。此外，抗原受体在T细胞上的接合导致S1P1 mRNA表达的转录下调和延长的淋巴细胞出口抑制作用。因此，在免疫反应的早期阶段，S1P1功能受两个不同的机制严格调节。该提案的目的是进一步了解S1P1和CD69对淋巴细胞运输的调节及其对T细胞反应产生的影响。细胞和生化方法将用于确定：（1）S1P1-CD69相互作用的分子需求； （2）CD69抑制S1P1功能的分子机制； （3）S1P1表达调节和功能对病毒感染的体内T细胞反应的遗传扰动的影响。我们的希望是，对调节淋巴细胞运输的因素有详细的理解不仅可以促进疫苗的发育和改善的免疫疗法，而且还为自身免疫性和慢性炎症性疾病中这些过程的治疗破坏提供了靶标。公共卫生相关性：白细胞通过淋巴组织的循环对于对感染性微生物（例如病毒）的免疫反应至关重要，但在慢性炎症性和自身免疫性疾病中也可能造成不利的后果。该提案的目的是详细了解如何影响白细胞运输的两个特定分子调节这一过程。从这些研究中获得的知识将有助于开发针对白细胞运输以治疗炎症性疾病的疗法。