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.
Statement This proposal is focused upon elucidating the fundamental mechanisms that govern bacterial carbohydrate structure, function, and specificity during interactions with host immune proteins. A biophysical understanding of carbohydrate structure and the specific molecular contacts they form that facilitate protective immunity will serve as a foundation to develop novel carbohydrate-based vaccines against a number of infectious microorganisms.
| Johnson, Jenny L; Jones, Mark B; Cobb, Brian A (2018) Polysaccharide-experienced effector T cells induce IL-10 in FoxP3+ regulatory T cells to prevent pulmonary inflammation. Glycobiology 28:50-58 |
| Zhou, Julie Y; Oswald, Douglas M; Oliva, Kelsey D et al. (2018) The Glycoscience of Immunity. Trends Immunol 39:523-535 |
| Oliva, Kelsey D; Cavanaugh, Jill M; Cobb, Brian A (2018) Antibody receptors steal the sweet spotlight. J Biol Chem 293:3490-3491 |
| Hiyoshi, Hirotaka; Wangdi, Tamding; Lock, Gabriel et al. (2018) Mechanisms to Evade the Phagocyte Respiratory Burst Arose by Convergent Evolution in Typhoidal Salmonella Serovars. Cell Rep 22:1787-1797 |
| Jun, Janice C; Jones, Mark B; Oswald, Douglas M et al. (2017) T cell-intrinsic TLR2 stimulation promotes IL-10 expression and suppressive activity by CD45RbHi T cells. PLoS One 12:e0180688 |
| Jones, Mark B; Ryan, Sean O; Johnson, Jenny L et al. (2016) Dendritic cell-specific Mgat2 knockout mice show antigen presentation defects but reveal an unexpected CD11c expression pattern. Glycobiology 26:1007-1013 |
| Jones, Mark B; Oswald, Douglas M; Joshi, Smita et al. (2016) B-cell-independent sialylation of IgG. Proc Natl Acad Sci U S A 113:7207-12 |
| Johnson, Jenny L; Jones, Mark B; Cobb, Brian A (2015) Polysaccharide A from the capsule of Bacteroides fragilis induces clonal CD4+ T cell expansion. J Biol Chem 290:5007-14 |
| Johnson, Jenny L; Jones, Mark B; Cobb, Brian A (2015) Bacterial capsular polysaccharide prevents the onset of asthma through T-cell activation. Glycobiology 25:368-75 |
| Ryan, Sean O; Leal Jr, Sixto M; Abbott, Derek W et al. (2014) Mgat2 ablation in the myeloid lineage leads to defective glycoantigen T cell responses. Glycobiology 24:262-71 |
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