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.
This proposal is focused upon elucidating the fundamental mechanisms that govern bacterial carbohydrate function and specificity during interactions with host immune proteins. A biophysical understanding of carbohydrate antigens and the specific molecular contacts they form that facilitate adaptive immunity will serve as a foundation for understanding the role these glycoantigens play in a host of disease states ranging from arthritis and some forms of cancer to inflammatory bowel disease.
Showing the most recent 10 out of 25 publications
