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）：免疫系统在检测和启动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。影响淋巴细胞进入和退出这些淋巴组织的因素尚不完全清楚。此外，淋巴细胞再循环的持续病理性破坏可导致淋巴器官中淋巴细胞的隔离，如 HIV 感染中所见，并可能导致宿主的免疫抑制。我们研究计划的长期目标是使用病毒感染作为模型系统，获得对急性和慢性炎症中淋巴细胞运输调节的详细分子理解。我们发现，淋巴细胞内磷脂受体 1-磷酸鞘氨醇受体 1 (S1P1) 的表达是淋巴细胞从次级淋巴器官排出的能力所必需的。先天性和适应性免疫反应都会改变该受体的表达和功能，导致淋巴细胞隔离。多种细胞因子，包括干扰素 α/β (IFN)，上调跨膜 C 型凝集素 CD69 的表达。 CD69 与 G 蛋白偶联受体 S1P1 相互作用并下调其表面表达和功能，导致短暂的淋巴细胞隔离。此外，T 细胞上的抗原受体的结合导致 S1P1 mRNA 表达的转录下调和淋巴细胞流出的长期抑制。因此，在免疫反应的早期阶段，S1P1 功能受到两种不同机制的严格调节。该提案的目标是进一步了解 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。将利用细胞和生化方法来确定：（1）S1P1-CD69相互作用的分子要求； (2)CD69抑制S1P1功能的分子机制； (3) S1P1 表达和功能调节的遗传扰动对体内 T 细胞对病毒感染反应的影响。我们希望，对调节淋巴细胞运输的因素的详细了解不仅有助于疫苗的开发和改进的免疫疗法，而且还可以为自身免疫和慢性炎症性疾病中这些过程的治疗破坏提供目标。公共卫生相关性：白细胞通过淋巴组织的循环对于启动针对病毒等传染性微生物的免疫反应至关重要，但也可能对慢性炎症和自身免疫性疾病产生有害后果。该提案的目标是详细了解已知影响白细胞运输的两种特定分子如何调节这一过程。从这些研究中获得的知识将有助于开发针对白细胞运输的治疗炎症性疾病的疗法。