Antigenic Carbohydrate Structure, Function, and Specificity

描述（由申请人提供）：益生菌是以某种方式赋予其宿主益处的活生物体。脆弱拟杆菌是一种这样的益生菌，凭借其荚膜多糖PSA的免疫调节特性，PSA是一类新的MHC II类呈递的碳水化合物T细胞抗原（糖抗原）的创始成员。在gnotobiotic小鼠中口服暴露于PSA恢复了Th 1/Th 2平衡和免疫稳态，同时通过诱导调节性T细胞使这些动物对炎症性疾病不那么敏感。我们发表的和初步的数据进一步证明，N-连接的聚糖装饰抗原呈递细胞，特别是MHCII的性质，是一个关键方面的机制，糖抗原提出和识别的T细胞。这些创新和意外的发现表明，免疫稳态可以通过宿主聚糖对肿瘤特异性Treg细胞诱导的影响而通过细胞糖基化来调节。在这里，我们提出了三个具体的目标，以获得一个完整的机制和结构的理解如何主机糖基化调节糖抗原呈递，外周炎症，并最终在分子，细胞和有机体水平的免疫稳态。我们提出的实验结果将揭示炎症和糖基化之间通过碳水化合物抗原活性的调节联系，并可能导致药物靶点识别，以预防和/或治疗哮喘，IBD，动脉粥样硬化和癌症等疾病中的持续炎症。

DESCRIPTION (provided by applicant): Probiotics are live organisms that confer a benefit to their host in some fashion. Bacteroides fragilis is one such probiotic by virtue of the immunomodulatory properties of its capsular polysaccharide PSA, the founding member of a novel class of MHC class II-presented carbohydrate T cell antigens (glycoantigens). Oral exposure to PSA in gnotobiotic mice restores the Th1/Th2 balance and immune homeostasis while rendering these animals less susceptible to inflammatory diseases through the induction of regulatory T cells. Our published and preliminary data further demonstrate that the nature of the N-linked glycans decorating antigen presenting cells, and specifically MHCII, is a critical aspect of the mechanism by which glycoantigens are presented and recognized by T cells. These innovative and unexpected findings suggest that immune homeostasis could be regulated by cellular glycosylation by virtue of the impact host glycans have on the induction of commensal-specific Treg cells. Here, we propose three specific aims to obtain a complete mechanistic and structural understanding of how host glycosylation modulates glycoantigen presentation, peripheral inflammation, and ultimately immune homeostasis at the molecular, cellular, and organismal levels. The results from our proposed experiments will reveal regulatory connections between inflammation and glycosylation through carbohydrate antigen activity and could lead to drug target identification to prevent and/or treat ongoing inflammation in diseases as diverse as asthma, IBD, atherosclerosis, and cancer.