Biochemistry of Antigen Presentation Mechanisms

描述（由申请人提供）：据信用于抗原加工、呈递和T细胞活化的II类主要组织相容性复合体（MHCII）途径仅限于蛋白质抗原。因此，所有已知的疫苗都利用蛋白质来产生长期的免疫保护。然而，已发表的工作现在已经将来自包封细菌如金黄色葡萄球菌的两性离子荚膜多糖（ZPS）鉴定为一类新的MHCII依赖性蛋白。 T细胞抗原最近的数据进一步表明，ZPS抗原在抗原呈递细胞中通过氧化加工成小片段，然后与MHCII蛋白结合。为了开始定义这个新扩展的MHCII范例中的关键步骤，已经设计了两个具体目标。(1)氧化介导的多糖抗原加工的分析：探索宿主对包囊细菌反应期间ZPS加工中氧化剂产生的作用。(2)多糖T细胞依赖性抗原的MHCII结合位点的表征：在ZPS抗原结合期间MHCII蛋白的关键接触的鉴定。ZPS抗原被氧化剂处理的方式以及MHCII结合期间产生的接触代表了针对包囊细菌的适应性免疫应答和疫苗设计研究的新前沿。这些结果甚至可以为增强T细胞对其他碳水化合物的反应提供生化基础。K22奖将促进我获得终身教职的直接目标，通过在竞争性面试过程中给我显著的动力和市场化。更重要的是，它将帮助我发展我作为一名独立科学家的早期职业生涯，致力于将传统的生物化学和生物物理学应用于免疫学问题，并对合理的治疗设计特别感兴趣。从这个角度来看，这些研究代表了我作为一名生物化学研究生和一名研究免疫学和发病机制的研究员的教育目标的顶峰。

DESCRIPTION (provided by applicant): The class II major histocompatibility complex (MHCll) pathway for antigen processing, presentation and T cell activation is believed to be limited to protein antigens. As a result all known vaccines utilize proteins to generate long-term immune protection. However, published work has now identified zwitterionic capsular polysaccharides (ZPSs) from encapsulated bacteria like Staphylococcus aureus as a new class of MHCII-dependent T-cell antigens. Recent data further demonstrates that ZPS antigens are processed to small fragments in antigen presenting cells through oxidation and then associate with MHCII proteins. To begin defining the key steps in this newly expanded MHCII paradigm, two specific aims have been designed. (1) Analysis of oxidation-mediated polysaccharide antigen processing: exploration of the role(s) of oxidant production in ZPS processing during host responses to encapsulated bacteria. (2) Characterization of the MHCII binding site for polysaccharide T cell-dependent antigens: identification of key contacts on MHCII proteins during ZPS antigen binding. The manner in which ZPS antigens are processed by oxidants together with the contacts made during MHCII binding represent new frontiers in the study of adaptive immune responses and vaccine design against encapsulated bacteria. These results may even provide the biochemical basis for the enhancement of T cell responses against other carbohydrates. The K22 award would facilitate my immediate goal of obtaining a tenure-track academic appointment by giving me significant momentum and marketability in the competitive interview process. More importantly, it would help me to develop my early career as an independent scientist working to apply traditional biochemistry and biophysics to immunological questions, with particular long-term interests in rational therapeutic design. From this point of view, the proposed studies represent the culmination of my educational goals as a biochemistry graduate student and a fellow studying immunology and pathogenesis.