Antigenic Carbohydrate Structure, Function, and Specificity

点击翻译按钮获取中文摘要

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.