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.

项目总结/摘要 对伯氏疏螺旋体的免疫应答是复杂的，有时是神秘的。大多数的研究 关于莱姆病免疫学的研究都集中在大量脂蛋白的作用上， 在螺旋体中。我们已经证明了B.伯氏菌具有独特的糖脂（MGal）和胆固醇糖脂 （CGal）具有重要的生物学和结构特性，并且包括诱导 抗体的γ-δ（γδ）T细胞跨越先天性和适应性免疫，并且众所周知其响应于免疫应答。 脂质抗原，但反应性只有很少被证明对一个特定的细菌脂质抗原。 基于该信息，我们测试了MGal和CGal刺激能够活化T细胞的特化γδ T细胞的活性。 长期记忆形成和干扰素γ（IFNγ）和IL-17 A的共同产生，这些细胞因子对于 抗病原体免疫令人惊讶的是，MGal在诱导IFNγ和IFN β方面几乎与活的疏螺旋体一样有效。 IL-17 A来自这些非常规T细胞。这些发现导致了这一建议，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 免疫力将使用无偏和大规模细胞因子高通量评价γδ T细胞的功能 体外和小鼠试验，此后，我们计划一种机制方法来评估这些疏螺旋体脂质如何 引发γδ T细胞功能性应答。鉴于莱姆病免疫反应的复杂性， 将探索不同的γδ T细胞亚群在对B的反应中的作用。伯氏感染脂质的方式- 将确定引发的γδ Τ细胞功能，并且将确定γδ Τ细胞的相应功能应答。 机械地评价。我们预期γδ T细胞-疏螺旋体轴将是导致疏螺旋体感染的重要因素。 莱姆病的免疫反应