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

基本信息

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
项目类别：
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

项目摘要

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称为荚膜多糖（CPS）的表面碳水化合物。 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物疫苗基于反复试验，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) 表面的复杂 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富含功能性 Tcarb 表位的基于知识的糖复合物疫苗。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。