Glycobiology Advance Access published online on June 4, 2008
Glycobiology, doi:10.1093/glycob/cwn050
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Characteristics of Carbohydrate Antigen Binding to the Presentation Protein HLA-DR
1 Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH
2 Channing Laboratory, Department. of Medicine, Brigham &, Women's Hospital, Boston, MA
* Correspondence: Brian A. Cobb, Department of Pathology, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106–7288, Tel. (216) 368–1263, Fax (216) 368–0494, email: brian.cobb{at}case.edu
Zwitterionic polysaccharide antigens (ZPSs) were recently shown to activate T cells in a class II major histocompatibility complex (MHCII)-dependent fashion requiring antigen presenting cell (APC)-mediated oxidative processing, although little is known about the mechanism or affinity of carbohydrate presentation.[Cobb et al., 2004] A recent study showed that the helical conformation of ZPSs [Choi et al., 2002;Wang et al., 2000] is closely linked with immunogenic activity [Tzianabos et al., 1993] and is stabilized by the zwitterionic charge motif [Kreisman et al., 2007], suggesting a strong carbohydrate structure-function relationship. In this study, we show that PSA, the ZPS from Bacteroides fragilis, associates with MHCII at high affinity and 1:1 stoichiometry through a mechanism mirroring peptide presentation. Interestingly, PSA binding was mutually exclusive with common MHCII antigens and showed significant allelic differences in binding affinity. The antigen exchange factor HLA-DM that catalyzes peptide antigen association with MHCII also increased the rate of ZPS association and was required for APC presentation and ZPS-mediated T cell activation. Finally, the zwitterionic nature of these antigens was required only for MHCII binding, and not endocytosis, processing, or vesicular trafficking to MHCII-containing vesicles. This report is the first quantitative analysis of the binding mechanism of carbohydrate antigens with MHCII and leads to a novel model for non-traditional MHCII antigen presentation during bacterial infections.
Key words: MHCII presentation / carbohydrate / antigen binding / antigen processing
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