Antigenic Carbohydrate Structure, Function, and Specificity

细菌多糖传统上被认为是不形成稳定二级结构的分子， 结构，并且不能引发保护性T淋巴细胞驱动的免疫应答。我们有 最近发现，一类多糖不仅通过类 II型主要组织相容性复合体（MHCII）介导的呈递，但它也需要一个 稳定的螺旋结构与MHCII相关。这些“糖抗原”与肽竞争， 与MHCII结合的抗原，表明它们与关键肽结合形成接触， 沟定位氨基酸。此外，初步数据表明，N-连接聚糖 MHCII蛋白对于糖抗原的适当结合和呈递至关重要， 而不是常规的肽抗原。这些结果导致了一个假设，即识别和 适应性免疫系统对糖抗原的呈递是特异性的， MHCII蛋白和N-聚糖接触。因此，本提案旨在阐明 控制MHCII结合和特异性的基本生物物理机制， 通过定义MHCII蛋白骨架的贡献， (Aim 1）和MHCII N-连接聚糖（Aim 2）。这些研究提供了一个独特的机会， 迅速扩大我们目前有限的知识，碳水化合物的功能，在基本的适应 通过提供对细菌病原体的生物物理理解， 糖抗原表位和它们在产生所需的关键免疫复合物中的接触 保护性免疫反应

Bacterial polysaccharides are traditionally viewed as molecules that do not form stable secondary structure and are unable to elicit a protective T lymphocyte-driven immune response. We have recently discovered that one class of polysaccharide not only activates a T cell response via class II major histocompatibility complex (MHCII)-mediated presentation, but that it also requires a stable helical structure to associate with MHCII. These "glycoantigens" compete with peptide antigens for association with MHCII, suggesting that they form contacts with key peptide binding groove-localized amino acids. Moreover, preliminary data implicates the N-linked glycans on MHCII proteins as being critical for appropriate binding and presentation of glycoantigens but not conventional peptide antigens. These results have led to the hypothesis that recognition and presentation of glycoantigens by the adaptive immune system is specific and relies upon unique MHCII protein and N-glycan contacts. As a result, this proposal is designed to elucidate the fundamental biophysical mechanisms that govern MHCII binding and specificity during glycoantigen presentation through defining the contributions of the MHCII protein backbone (Aim 1) and MHCII N-linked glycans (Aim 2). These studies represent a unique opportunity to rapidly expand our currently limited knowledge of carbohydrate function in fundamental adaptive immune mechanisms against bacterial pathogens by providing the biophysical understanding of glycoantigen epitopes and the contacts they make in key immune complexes required to produce protective immune responses.