Antigenic Carbohydrate Structure, Function, and Specificity

描述（由申请人提供）：益生菌是一种以某种方式对宿主有益的活生物体。脆弱拟杆菌就是这样一种益生菌，它的荚膜多糖PSA具有免疫调节特性，PSA是一类新的MHC ii类碳水化合物T细胞抗原（糖抗原）的创始成员。通过诱导调节性T细胞，使小鼠口服暴露于PSA恢复Th1/Th2平衡和免疫稳态，同时使这些动物对炎症性疾病的易感性降低。我们发表的和初步的数据进一步表明，修饰抗原呈递细胞，特别是MHCII的n -链聚糖的性质，是糖抗原被T细胞呈递和识别的机制的一个关键方面。这些创新和意想不到的发现表明，细胞糖基化可能通过宿主聚糖对诱导共生特异性Treg细胞的影响来调节免疫稳态。在这里，我们提出了三个特定的目标，以获得宿主糖基化如何在分子、细胞和组织水平上调节糖抗原呈递、外周炎症和最终免疫稳态的完整机制和结构理解。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鉴定，以预防和/或治疗哮喘、IBD、动脉粥样硬化和癌症等多种疾病的持续炎症。

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.