Antibody responses against bacterial glycans affinity mature and diversify in germinal centers

Anti-carbohydrate antibodies (Abs) play crucial roles in pathogen control, but their generation remains poorly understood. Here, we studied how B cell immunity against the Streptococcus pyogenes surface polysaccharide is influenced by age and antigen (Ag) exposure across human blood, spleen, and tonsils. The glycan-targeted response shifted from immunoglobulin M (IgM) biased in children toward IgG and IgA biased in adults. Both natural colonization and controlled human infection with S. pyogenes increased class-switched B cells, with evidence of within-clone switching. Glycan-specific B cells readily engaged in germinal center (GC) responses and underwent robust somatic hypermutation (SHM) but had reduced expression of T cell help-associated molecules, correlating with lower antibody-secreting cell (ASC) output. Thus, mucosal pathogen encounters elicit glycan responses that class switch, evolve, and diversify through the GC, with implications for the design and schedule of glycan-containing vaccines.