Molecular Mechanisms for Carbohydrate Presentation to CD4+ T cells by MHCII Pathway

通过 MHCII 途径将碳水化合物呈递给 CD4 T 细胞的分子机制

• 批准号: 9285694
• 负责人: Fikri Y Avci
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-06 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9285694
• 关键词: APC Vaccine; Adaptive Immune System; Adoptive Transfer; Antibodies; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Bacteria; Bacterial Infections; Bacterial Model; Bacterial Polysaccharides; Binding; Biological; Biological Assay; CD4 Positive T Lymphocytes; Carbohydrates; Carrier Proteins; Cell surface; Cells; Chemicals; Chemistry; Clone Cells; Communicable Diseases; Competitive Binding; Complex; Comprehension; Conjugate Vaccines; Data; Disaccharides; Epitopes; Future; Generations; Glycoconjugates; Health; Health Benefit; Helper-Inducer T-Lymphocyte; Histocompatibility Antigens Class II; Human; Immune; Immune response; Immune system; Immunization; Immunoglobulin Class Switching; Immunoglobulin G; Immunologic Surveillance; Knowledge; Libraries; Major Groove; Mass Spectrum Analysis; Measurement; Mediating; Methods; Modeling; Modification; Molecular; Mus; Oligosaccharides; Pathogenicity; Pathway interactions; Peptides; Play; Polysaccharides; Population; Process; Production; Property; Proteins; Role; Streptococcus pneumoniae; Structure; Surface; Surface Antigens; System; T-Cell Receptor; T-Lymphocyte; T-Lymphocyte Epitopes; TCR Activation; Time; Vaccine Design; Vaccine Research; Vaccines; adaptive immune response; base; clinical practice; cost; depolymerization; design; experimental study; high risk population; immune activation; immunogenic; insight; knowledge base; mimetics; novel; older patient; pathogenic bacteria; peptide I; response; uptake; vaccine candidate

Project Summary/Abstract Most pathogenic bacteria express surface carbohydrates called capsular polysaccharides (CPSs). CPSs are important vaccine candidates given that they are located on the outermost surface of bacteria and they have distinct structures. These two features make them easily accessible and distinctly recognizable by immune surveillance, therefore resulting in production of CPS specific antibodies by B cells. To induce a CPS specific adaptive immune response (i.e., T cell-mediated B cell response), CPSs are conjugated with carrier proteins, and the conjugation products are called glycoconjugate vaccines. Due to insufficient understanding of their immune activation mechanisms, current glycoconjugate vaccine strategies have reached saturation and are largely modifications of past empirical conjugation methods. The production of the current generation of glycoconjugate vaccines is based on trial and error and does not make use of specific scientific knowledge to maximize stimulation of critical immune cells (i.e., helper T cells) involved in producing protective IgG antibodies. A new perspective to carbohydrate-based vaccine research is much needed. With the potential of establishing a new paradigm, our previous discovery and preliminary data demonstrate that the mammalian CD4+ T cell repertoire contains a population of carbohydrate-specific T cells (i.e., Tcarbs) that recognize carbohydrate epitopes. Here, we propose to expand on our previous discovery and define the molecular mechanisms for Tcarb activation by carbohydrate epitopes from a model glycoconjugate vaccine. In Aim 1 of this proposal we will elucidate structural requirements for carbohydrate presentation by major histocompatibility complex class II (MHCII) proteins on the surface of antigen presenting cells (APCs) or as purified MHCII proteins via interaction studies. In Aim 2 we will structurally and functionally characterize T cell receptor (TCR) recognition of glycan epitopes by Tcarbs. We believe our proposed studies will create a new platform to develop knowledge-based glycoconjugate vaccines that are enriched for functional Tcarb epitopes. Using the discovery of Tcarb activation mechanisms and of structures of glycan epitopes, we can design and develop new-generation glycoconjugate vaccines that will elicit strong and long lasting immune response to protect from bacterial infections.

项目概要/摘要 大多数病原菌表达表面碳水化合物，称为荚膜多糖（CPS）。 CPS 是 重要的候选疫苗，因为它们位于细菌的最外层表面，并且具有 不同的结构。这两个特征使它们易于被免疫系统识别并易于访问 监视，因此导致 B 细胞产生 CPS 特异性抗体。诱导 CPS 特异性 适应性免疫反应（即 T 细胞介导的 B 细胞反应），CPS 与载体蛋白缀合， 结合产物称为糖结合疫苗。由于对自己的了解不够 免疫激活机制，目前的糖复合物疫苗策略已达到饱和， 很大程度上修改了过去的经验共轭方法。当前一代的生产 糖复合疫苗基于反复试验，不利用特定的科学知识 最大限度地刺激参与产生保护性 IgG 的关键免疫细胞（即辅助 T 细胞） 抗体。基于碳水化合物的疫苗研究非常需要新的视角。具有潜力 建立一个新的范式，我们之前的发现和初步数据表明，哺乳动物 CD4+ T 细胞库包含一群碳水化合物特异性 T 细胞（即 Tcarb），可识别 碳水化合物表位。在这里，我们建议扩展我们之前的发现并定义分子 糖复合物疫苗模型中碳水化合物表位激活 Tcarb 的机制。目标 1 该提案我们将通过主要组织相容性阐明碳水化合物呈现的结构要求 抗原呈递细胞 (APC) 表面的复合 II 类 (MHCII) 蛋白或纯化的 MHCII 蛋白 通过相互作用研究的蛋白质。在目标 2 中，我们将从结构和功能上表征 T 细胞受体 (TCR) Tcarbs 识别聚糖表位。我们相信我们提出的研究将创建一个新的平台 开发基于知识的复合糖疫苗，该疫苗富含功能性 Tcarb 表位。使用 发现 Tcarb 激活机制和聚糖表位结构，我们可以设计和开发 新一代糖复合物疫苗将引发强烈且持久的免疫反应以保护 来自细菌感染。