Structural Immunology of CD1 and CD1-TCR Complexes

CD1 和 CD1-TCR 复合物的结构免疫学

• 批准号: 7769934
• 负责人: Dirk M Zajonc
• 金额: $ 40.76万
• 依托单位: LA JOLLA INSTITUTE FOR IMMUNOLOGY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7769934
• 关键词: 1,2-diacylglycerol; Address; Adjuvant; Amino Acids; Antibodies; Antigen Presentation; Antigen Receptors; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune Diseases; Autoimmunity; Binding; Biochemical; Biological Models; Biology; Borrelia burgdorferi; Brain; CD1 Antigens; CD4 Positive T Lymphocytes; Cells; Cellular Immunity; Ceramides; Complex; Crystallography; Cytotoxic T-Lymphocytes; Data; Development; Diglycerides; Disease; Docking; Epitopes; Experimental Autoimmune Encephalomyelitis; Future; Galactosylceramides; Glycerol; Glycolipids; Glycosphingolipids; Goals; Health; Helper-Inducer T-Lymphocyte; Hexoses; Host Defense; Human; Hybridomas; Immune; Immune response; Immune system; Immunology; Infection; Infectious Agent; Kinetics; Light; Link; Lipids; Lyme Disease; Lymphocyte; MHC Class I Genes; Measures; Modeling; Modification; Molecular; Molecular Structure; Multiple Sclerosis; Mus; Mutagenesis; Order Spirochaetales; Organism; Outcome; Peptides; Phospholipids; Play; Production; Property; Recruitment Activity; Roentgen Rays; Role; Series; Side; Specificity; Structure; Sulfoglycosphingolipids; Surface Plasmon Resonance; T-Cell Activation; T-Cell Receptor; T-Lymphocyte; TCR Activation; Type II Epithelial Receptor Cell; Vertebral column; antigen binding; base; carbene; cell type; chemotherapeutic agent; combat; cytokine; field study; insight; interest; killings; lipid structure; microbial; microorganism antigen; novel; preference; public health relevance; response; sugar; three dimensional structure; tumor; unsaturated bonds

DESCRIPTION (provided by applicant): Over the past 10 years, a tremendous amount of data has accumulated, which demonstrates the role of glycolipid-reactive T cells in autoimmune disease, host defense and tumor development. T cells and NKT cells can respond to a broad pool of self and foreign antigens presented by CD1 molecules and can trigger killing of the antigen presenting cell, through cytotoxic T lymphocytes (CTLs), or recruit help (T helper cells) from the humoral immune system through production of soluble antibodies. Our lab is interested in the molecular mechanisms of lipid antigen recognition in cell-mediated immunity. Toward this goal, we determine the binding kinetics of various glycolipid- reactive T cell receptor's (TCR's) with various CD1 antigen-presenting molecules by surface plasmon resonance studies (SPR). We will further correlate the obtained results with data obtained by measuring cytokine production upon T cell activation using T cell hybridomas. Ultimately we propose to determine the three-dimensional structure of CD1 antigen receptors in complex with different lipids and cognate T cell receptors (TCR's) by x-ray crystallography. We specifically address the following specific aims: 1) What are the biochemical and functional properties of human and mouse sulfatide-reactive NKT cells. We will determine the structure of sulfatide loaded human CD1a and mouse CD1d in complex with the respective TCR and characterize their binding kinetics by SPR. Comparisons of both complexes will provide insights into the similarities and disparities of sulfatide recognition by the immune system and will shed light on the molecular mechanism of their activation. 2) We will structurally and functionally characterize differences in glycolipid recognition of Borrelia burgdorferi glycolipids by human and mouse NKT cells. 3) We will characterize binding of novel endogenous self-lipids to mouse CD1d and their recognition by NKT cells. Structural insights into the differences of self vs. microbial antigen presentation will help understand the role of microbial lipids and lipid-reactive T cells in host defense and autoimmune diseases. Public Health Relevance: NKT cells are specialized lymphocytes that consist of several subtypes and can respond to glycolipids from infectious organisms, such as Borrelia burgdorferi the causative agent of Lyme disease and self-lipids, during the course of autoimmune disease such as Multiple sclerosis. Understanding the functional properties of these cell types at a molecular level is crucial for the future development of novel chemotherapeutic agents or adjuvants to combat both diseases.

描述（申请人提供）：在过去的10年里，积累了大量的数据，证明了糖脂反应性T细胞在自身免疫性疾病、宿主防御和肿瘤发展中的作用。 T 细胞和 NKT 细胞可以对 CD1 分子呈递的大量自身和外来抗原作出反应，并可以通过细胞毒性 T 淋巴细胞 (CTL) 触发抗原呈递细胞的杀伤，或从体液免疫中招募帮助（T 辅助细胞）通过产生可溶性抗体的系统。我们的实验室对细胞介导的免疫中脂质抗原识别的分子机制感兴趣。为了实现这一目标，我们通过表面等离子共振研究 (SPR) 确定了各种糖脂反应性 T 细胞受体 (TCR) 与各种 CD1 抗原呈递分子的结合动力学。我们将进一步将获得的结果与使用 T 细胞杂交瘤测量 T 细胞激活时细胞因子产生所获得的数据相关联。最终，我们建议通过 X 射线晶体学确定 CD1 抗原受体与不同脂质和同源 T 细胞受体 (TCR) 复合物的三维结构。我们具体解决以下具体目标：1）人和小鼠脑硫苷脂反应性 NKT 细胞的生化和功能特性是什么。我们将确定载有硫苷脂的人 CD1a 和小鼠 CD1d 与各自 TCR 的复合物的结构，并通过 SPR 表征它们的结合动力学。两种复合物的比较将深入了解免疫系统识别脑硫苷脂的相似性和差异，并揭示其激活的分子机制。 2) 我们将从结构和功能上表征人类和小鼠 NKT 细胞对伯氏疏螺旋体糖脂识别的差异。 3) 我们将表征新型内源性自脂与小鼠 CD1d 的结合及其被 NKT 细胞的识别。对自身与微生物抗原呈递差异的结构了解将有助于了解微生物脂质和脂质反应性 T 细胞在宿主防御和自身免疫性疾病中的作用。公共健康相关性：NKT 细胞是一种特殊的淋巴细胞，由多种亚型组成，在多发性硬化症等自身免疫性疾病的过程中，可以对传染性生物体（例如莱姆病的病原体伯氏疏螺旋体）和自身脂质产生反应。在分子水平上了解这些细胞类型的功能特性对于未来开发对抗这两种疾病的新型化疗剂或佐剂至关重要。