Alternative mechanism for glycoconjugate vaccine activation of the adaptive immune system (52.25)

Abstract

Abstract Glycoconjugate vaccines, which are currently made by covalently coupling a bacterial capsular polysaccharide to a carrier protein, have been used to immunize many millions of people and have enormously reduced disease burden, particularly among children. However, the immunogenicity and efficacy of these vaccines have been relatively low and heterogeneous in some high-risk populations. The classic antigen presentation hypothesis for glycoconjugates proposes that helper CD4+ T cells recognize a peptide derived from the carrier protein. We investigated mechanisms of processing and presentation of a prototypic glycoconjugate vaccine in which group B streptococcal type III polysaccharide is coupled to a carrier. Upon uptake into the endosome of an antigen-presenting cell, the polysaccharide undergoes oxidative depolymerization, which, in conjunction with acidic protease-mediated digestion of the carrier protein, creates a carbohydrate T cell epitope conjugated to an MHCII binding peptide. These epitopes formed in the endosome bind to MHCII through the peptide and are subsequently presented on the APC surface, with the hydrophilic carbohydrate positioned for easy recognition by the T-cell receptor. Recognition of the carbohydrate in the presence of MHCII drives T-cell help for antibody-producing B cells. An enhanced understanding of immune mechanisms such as T-cell recognition of carbohydrates may lead to markedly improved vaccines against infectious diseases.