Biochemistry of Antigen Presentation Mechanisms

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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.