Activation of T gamma/delta cells by Borrelia glycolipids

疏螺旋体糖脂激活 T γ/δ 细胞

• 批准号: 10418818
• 负责人: Jorge L. Benach
• 金额: $ 23.93万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-04 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10418818
• 关键词: Amino Acids; Antibodies; Antibody Formation; Antigens; Arbovirus Infections; Area; B-Cell Activation; B-Lymphocytes; Bacteria; Bacterial Antigens; Biological; Biological Assay; Blood Circulation; Borrelia; Borrelia burgdorferi; Cell physiology; Cells; Cellular biology; Cholesterol; Coculture Techniques; Complex; Confocal Microscopy; Emulsions; Epithelial; Etiology; Evaluation; Fatty Acids; Flow Cytometry; Formulation; Genome; Glycolipids; Homeostasis; Immune; Immune response; Immunity; Immunologics; Immunology; In Vitro; Infection; Interferon Type II; Interleukin-17; Kinetics; Laboratories; Lipids; Lipoproteins; Liposomes; Lyme Disease; Membrane; Memory; Methodology; Modeling; Mucous Membrane; Mus; Natural Immunity; Nature; Order Spirochaetales; Organic solvent product; Pathway interactions; Phenotype; Population; Preparation; Process; Production; Prokaryotic Cells; Property; Proteins; Proteome; Role; Site; Skin; Sonication; Source; Stains; Synovial Membrane; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; United States; adaptive immune response; adaptive immunity; aqueous; base; cytokine; high throughput screening; in vitro Assay; in vivo; insight; microbial; pathogen; pathogenic bacteria; response; tool; γδ T cells

PROJECT SUMMARY/ABSTRACT The immune response to Borrelia burgdorferi is complex and at times, enigmatic. Most of the studies that have been done on the immunology of Lyme disease have focused on the role of the lipoproteins that are abundant in the spirochetes. We have shown that B. burgdorferi has unique glycolipids (MGal) and cholesteryl glycolipids (CGal) that have important biological and structural properties and include the ability to induce formation of antibodies. Gamma-delta (γδ) T cells straddle innate and adaptive immunity and are well known for responding to lipid antigens, but responsiveness has only rarely been demonstrated toward a specific bacterial lipid antigen. Based on this information, we tested MGal and CGal for activity to stimulate a specialized γδ T cell capable of long-lived memory formation and co-production of interferon gamma (IFNγ) and IL-17A, cytokines important for anti-pathogen immunity. Surprisingly, MGal was nearly as efficient as live Borrelia in the induction of IFNγ and IL-17A from these nonconventional T cells. These findings led to this proposal whereby we will evaluate the the capacity for MGal and CGal preparations to activate distinct γδ T cell subsets that contribute to anti-pathogen immunity. The function of the γδ T cells will be evaluated using unbiased and large scale cytokine high throughput assays in vitro and in mice, and thereafter, we plan a mechanistic approach to evaluate how these Borrelia lipids elicit γδ T cell functional responses. Given the complexity of the immune response in Lyme disease, this proposal will explore the role of diverse γδ T cell subsets in the response to B. burgdorferi infection. The manner of lipid- elicited γδ T cell function will be determined, and the corresponding functional response of the γδ T cells will be evaluated mechanistically. We anticipate that the γδ T cell-Borrelia axis will be an important contributor to the immune response during Lyme disease.

项目摘要/摘要 对Burgdorferi的免疫反应很复杂，有时是神秘的。大多数研究 我们是在莱姆病免疫学上完成的，重点是丰富的脂蛋白的作用 在螺旋体中。我们已经证明B. burgdorferi具有独特的糖脂（MGAL）和胆固醇糖脂 （CGAL）具有重要的生物学和结构特性，包括诱导形成的能力 抗体。伽马 - 戴尔塔（γδ）T细胞跨越先天性和适应性免疫组织化学，并以响应而闻名 对于脂质抗原，但是很少证明反应性对特定的细菌脂质抗原。 基于此信息，我们测试了MGAL和CGAL的活性，以刺激专业的γδT细胞容量 干扰素伽马（IFNγ）和IL-17A的长期记忆形成和共同生产，细胞因子对 抗病原体免疫。令人惊讶的是，在诱导IFNγ和 这些非常规T细胞的IL-17a。这些发现导致了这一建议，我们将评估 MGAL和CGAL制剂的能力激活有助于抗病原体的不同γδT细胞子集 免疫。 γδT细胞的功能将使用无偏和大规模细胞因子高吞吐量评估 在体外和小鼠中进行测定，此后，我们计划了一种机械方法来评估这些毛脂脂如何 引起γδT细胞功能响应。鉴于莱姆病中免疫响应的复杂性，该提议 将探讨潜水员γδT细胞亚群在对B. burgdorferi感染的反应中的作用。脂质的方式 将确定引起的γδT细胞功能，并且γδT细胞的相应功能响应将为 机械评估。我们预计γδT细胞 - 波雷利亚轴将是造成 莱姆病期间的免疫反应。