Molecular basis of glycan recognition by T and B cells

T 和 B 细胞识别聚糖的分子基础

• 批准号: 10549648
• 负责人: Luc Teyton
• 金额: $ 45.42万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-09 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10549648
• 关键词: Address; Affinity; Antibiotic Resistance; Antibiotics; Antibodies; Antibody titer measurement; Antigenic Variation; Antigens; Automobile Driving; B cell repertoire; B-Lymphocytes; Bacteria; Bacterial Infections; Bacteriology; Binding; Biological Assay; Biological Testing; Biophysics; Blood; CD4 Positive T Lymphocytes; Cell Maturation; Cells; Chemicals; Chemistry; Child; Conjugate Vaccines; Development; Dimensions; Dissent; Elderly; Epitopes; Evaluation; Formulation; Generations; Germ-Line Mutation; Glycopeptides; Goals; Haemophilus influenzae; Haptens; Helper-Inducer T-Lymphocyte; Histocompatibility Antigens Class II; Immune; Immune response; Immune system; Immunity; Immunization; Immunologic Deficiency Syndromes; Immunology; Immunotherapy; Influenza B Virus; Intervention; Kidney; Kinetics; Knowledge; Link; Measurable; Modality; Modeling; Molecular; Monoclonal Antibodies; Morbidity - disease rate; Mus; Neisseria meningitidis; Passive Immunotherapy; Pathogenicity; Patients; Peptidoglycan; Phagocytosis; Polysaccharides; Population; Populations at Risk; Positioning Attribute; Process; Proteins; Race; Reagent; Recombinant Antibody; Recombinants; Serotyping; Staphylococcus aureus; Streptococcus pneumoniae; Structure; Structure of germinal center of lymph node; Surface; System; T cell response; T-Lymphocyte; Teichoic Acids; Transplantation; Vaccine Design; Vaccines; Work; biophysical analysis; design; diabetic; fighting; improved; in vivo; insight; man; microbial; microbiome; mortality; next generation; novel strategies; pathogen; prototype; receptor; response; structural biology; vaccination outcome; vaccine effectiveness; vaccine immunogenicity

Abstract While our PO1 aims at positioning anti-glycan immunotherapy as a new approach to treat severe bacterial diseases, we will contribute some essential basic studies to it by deconstructing the immune recognition of glycans by T and B cells. This work is made possible by the chemistry groups (Projects 1, 2, and 3) who will provide unique immunogens and reagents and will fit next to the bacteriology and structural biology components of the consortium to perform in vivo studies and structure determinations. The integration of the immunology results within this framework will inform the chemists on how to modify glycan epitopes and their linkages to optimize immune recognition and in vivo effector functions. Our effort will be divided between three specific aims: Aim 1: Establish the molecular basis of glycan recognition by T cells. We have shown that cognate recognition of the glycopeptide (GP) by T cells occurred. We will determine its importance in driving high affinity anti-glycan antibodies and study the repertoire diversity of these cells. The biophysical and structural basis of MHC-GP T cell recognition will be examined as well. We hypothesize that cognate glycan recognition by T cells is important for driving high affinity B cell maturation. Aim 2: Establish the molecular basis of glycan recognition by B cells. We will examine the kinetics of germinal center formation upon immunization and follow the maturation of anti- glycan B cells towards high affinity by isolating single B cells with antigen specific reagents and sequencing their receptors. Biophysical studies after recombinant expression of antibodies, paired with the structural effort of Core 3 should allow to decipher the basic rules of glycan antibody recognition. Here, recognition of capsular antigens will be compared to the recognition of teichoic acids, peptidoglycans and O-linked saccharides. Aim 3: Effectiveness of the vaccinal immune response to glycan in mice. As we evaluate in standard models the protection capacity of anti-glycan antibodies, we will compare vaccine to passive immunotherapy. The possibility to optimize this latter intervention will be explored with recombinant antibodies aimed at avoiding Staphylococcus aureus ability to foil the B cell response. While we have shown that we could produce monoclonal antibodies of high affinity against bacterial glycans protective in challenges models, here, we should provide fundamental mechanistic insights into the recognition of glycans by B and T cells. Our team will challenge this knowledge in the context of one of the most threatening bacterial infections of man: Staphylococcus aureus.

抽象的 虽然我们的 PO1 旨在将抗聚糖免疫疗法定位为治疗严重细菌性疾病的新方法 疾病，我们将通过解构免疫识别来为其贡献一些重要的基础研究 T 细胞和 B 细胞产生的聚糖。这项工作是由化学小组（项目 1、2 和 3）实现的，他们将 提供独特的免疫原和试剂，适合细菌学和结构生物学组件 该联盟进行体内研究和结构测定。免疫学的整合 该框架内的结果将告知化学家如何修饰聚糖表位及其与 优化免疫识别和体内效应器功能。我们的努力将分为三个具体目标： 目标 1：建立 T 细胞识别聚糖的分子基础。 我们已经证明，T 细胞发生了对糖肽 (GP) 的同源识别。我们将确定其 在驱动高亲和力抗聚糖抗体和研究这些细胞的库多样性方面具有重要意义。这 还将检查 MHC-GP T 细胞识别的生物物理和结构基础。我们假设 T 细胞的同源聚糖识别对于驱动高亲和力 B 细胞成熟非常重要。 目标 2：建立 B 细胞识别聚糖的分子基础。 我们将检查免疫后生发中心形成的动力学，并跟踪抗-细胞因子的成熟情况。 通过使用抗原特异性试剂分离单个 B 细胞并对其进行测序，使聚糖 B 细胞具有高亲和力 受体。抗体重组表达后的生物物理学研究，与 Core 的结构工作相结合 3 应允许破译聚糖抗体识别的基本规则。此处，荚膜抗原的识别 将与磷壁酸、肽聚糖和O-连接糖的识别进行比较。 目标 3：小鼠体内对聚糖的疫苗免疫反应的有效性。正如我们以标准评估的 为了模拟抗聚糖抗体的保护能力，我们将比较疫苗与被动免疫疗法。 将利用重组抗体探索优化后一种干预的可能性，以避免 金黄色葡萄球菌能够挫败 B 细胞反应。 虽然我们已经证明我们可以生产针对细菌聚糖具有高亲和力的单克隆抗体 挑战模型中的保护性，在这里，我们应该提供对识别的基本机制见解 B 细胞和 T 细胞的聚糖。我们的团队将在最具威胁性的环境之一的背景下挑战这一知识 人类细菌感染：金黄色葡萄球菌。