Activation of T gamma/delta cells by Borrelia glycolipids

项目摘要/摘要 对伯氏疏螺旋体的免疫反应是复杂的，有时是谜一样的。大多数研究都有 关于莱姆病的免疫学研究主要集中在丰富的脂蛋白的作用上 在螺旋体中。我们已经证明伯氏杆菌具有独特的糖脂(MgAl)和胆固醇糖脂。 (CGal)，具有重要的生物学和结构特性，包括诱导形成 抗体。伽马-三角洲(γδ)T细胞跨越先天免疫和获得性免疫，并以应答 对脂类抗原有反应，但对特定细菌脂类抗原的反应性很少。 基于这一信息，我们测试了镁铝和镁铝刺激一种特殊的γδT细胞的活性 长寿记忆的形成和干扰素γ和IL-17A的共同产生 抗病原体免疫。令人惊讶的是，镁铝在诱导干扰素γ和 这些非常规T细胞产生IL-17A。这些调查结果导致了这项建议，据此我们将评估 镁铝和镁铝制剂激活有助于抗病原体的γδT细胞亚群的能力 豁免权。γδT细胞的功能将使用无偏见和大规模的细胞因子高通量进行评估 在体外和在小鼠身上进行检测，然后，我们计划采用一种机械方法来评估这些疏螺旋体脂类如何 诱导γδT细胞功能反应。鉴于莱姆病免疫反应的复杂性，这项提议 将探索不同的γδT细胞亚群在应对伯氏杆菌感染中的作用。脂质的方式- 将确定激发的γδT细胞功能，并将相应的γδT细胞的功能应答 机械地评估。我们预计γδT细胞-疏螺旋体轴将是 莱姆病期间的免疫反应。

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.