Biochemistry of Antigen Presentation Mechanisms

描述(由申请人提供)：第二类主要组织相容性复合体(MHCll)的抗原处理、呈递和T细胞激活途径被认为仅限于蛋白质抗原。因此，所有已知的疫苗都利用蛋白质来产生长期免疫保护。然而，已发表的工作现已从金黄色葡萄球菌等被包裹的细菌中鉴定出两性胶囊多糖(ZPS)是一类新的MHCII依赖物质 T细胞抗原。最近的数据进一步表明，ZPS抗原通过氧化在抗原提呈细胞中被加工成小片段，然后与MHCII蛋白结合。为了开始确定这一新扩展的MHCII范式中的关键步骤，设计了两个具体目标。(1)氧化介导的多糖抗原加工的分析：探索氧化剂产生在ZPS加工中的作用(S)，在宿主对包裹细菌的反应中。(2)多糖类T细胞依赖抗原MHCII结合位点的鉴定：ZPS抗原结合过程中MHCII蛋白关键接触点的确定。ZPS抗原被氧化剂处理的方式，以及在MHCII结合期间产生的接触，代表了针对被包裹的细菌的适应性免疫反应和疫苗设计的研究的新前沿。这些结果甚至可能为增强T细胞对其他碳水化合物的反应提供生化基础。K22奖项将使我在竞争性面试过程中获得巨大的动力和市场空间，从而有助于我实现获得终身教职的直接目标。更重要的是，这将帮助我发展自己早期的职业生涯，成为一名独立科学家，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产生特别长期的兴趣。从这个角度来看，建议的研究代表了我作为一名生物化学研究生和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.