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: 9919487
• 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 2022-09-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919487
• 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; Cellular Structures; 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; Molecular Structure; 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; immune system function; 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.

项目摘要/摘要 大多数致病性细菌表达表面碳水化合物称为囊状多糖（CPSS）。 CPS是 重要的候选疫苗鉴于它们位于细菌的最外表面，并且具有 不同的结构。这两个功能使它们易于访问，并且可以通过免疫识别出明显的识别 因此，监测，导致B细胞生产CPS特异性抗体。诱导特定于CPS 自适应免疫反应（即T细胞介导的B细胞反应），CPS与载体蛋白相结合， 共轭产物称为糖缀合物疫苗。由于对他们的理解不足 免疫激活机制，当前的糖缀合物疫苗策略已达到饱和，已有 过去的经验共轭方法在很大程度上进行了修改。当前一代的生产 糖缀合疫苗是基于反复试验的，并且不利用特定的科学知识来 最大化参与保护性IgG的临界免疫细胞（即辅助T细胞） 抗体。非常需要对基于碳水化合物的疫苗研究的新观点。有潜力 建立新的范式，我们以前的发现和初步数据表明哺乳动物 CD4+ T细胞库中包含识别碳水化合物特异性T细胞（即TCARBS）的种群 碳水化合物表位。在这里，我们建议扩展我们以前的发现并定义分子 碳水化合物表位的TCARB激活的机制来自模型糖缀合物疫苗。在目标1中 该提案我们将通过主要的组织相容性阐明碳水化合物表现的结构要求 复杂的II类（MHCII）蛋白在抗原呈递细胞（APC）表面或纯化的MHCII上 通过相互作用研究蛋白质。在AIM 2中，我们将在结构和功能上表征T细胞受体（TCR） TCARBS对聚糖表位的识别。我们相信我们拟议的研究将创建一个新的平台 开发基于知识的糖缀合物疫苗，这些疫苗富含功能性TCARB表位。使用 发现TCARB激活机制和聚糖表位结构，我们可以设计和发展 新代糖缀合物疫苗将引起强烈而持久的免疫反应以保护 从细菌感染中。