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: 10301808
• 负责人: Jorge L. Benach
• 金额: $ 19.94万
• 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 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301808
• 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; Structure; 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.

项目概要/摘要 对伯氏疏螺旋体的免疫反应很复杂，有时甚至很神秘。大多数研究已经 对莱姆病免疫学的研究重点是丰富的脂蛋白的作用 在螺旋体中。我们已经证明伯氏疏螺旋体具有独特的糖脂 (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。 γ-δ (γδ) T 细胞跨越先天免疫和适应性免疫，并以响应能力而闻名 对脂质抗原，但对特定细菌脂质抗原的反应性很少得到证实。 基于这些信息，我们测试了 MGal 和 CGal 的活性，以刺激专门的 γδ T 细胞，该细胞能够 长效记忆的形成以及干扰素 γ (IFNγ) 和 IL-17A 的共同产生，这些细胞因子对于 抗病原体免疫力。令人惊讶的是，MGal 在诱导 IFNγ 和 IFNγ 方面几乎与活疏螺旋体一样有效。 来自这些非常规 T 细胞的 IL-17A。这些发现导致了这项提议，我们将评估 MGal 和 CGal 制剂激活有助于抗病原体的不同 γδ T 细胞亚群的能力 免疫。将使用公正且大规模的细胞因子高通量评估 γδ T 细胞的功能 在体外和小鼠中进行测定，此后，我们计划一种机械方法来评估这些疏螺旋体脂质如何 引发 γδ T 细胞功能反应。鉴于莱姆病免疫反应的复杂性，该提案 将探索不同 γδ T 细胞亚群在应对伯氏疏螺旋体感染的反应中的作用。脂质的方式—— 确定引发的 γδ T 细胞功能，并计算 γδ T 细胞相应的功能反应 机械地评价。我们预计 γδ T 细胞-疏螺旋体轴将成为 莱姆病期间的免疫反应。