Human anti-glycan reactivity emerges from B cells utilizing private gene rearrangements that are affinity maturated in germinal centers

The human antibody repertoire includes reactivity toward a broad array of carbohydrate antigens associated with commensal microflora and pathogenic organisms. Here, we examined the ontogeny and diversity of the human anti-glycan repertoire. Antibodies reactive with group A Streptococcus cell wall carbohydrate (GAC) were absent at birth but reached adult frequencies in childhood, concomitant with the emergence of circulating GAC-reactive memory B cells. GAC-binding B cells expressing germinal center (GC) markers were abundant in tonsil tissue from children. Recombinant antibodies derived from tonsillar GAC-binding B cells had diverse reactivity toward structurally similar hexosamine-containing glycans. Despite shared reactivity, expanded GAC-binding B cell lineages had diverse antigen receptor repertoires and somatic mutation signatures consistent with antigen selection and affinity maturation. Memory and marginal-zone (MZ)-like GAC-reactive B cells were derived from GC cells. Thus, the human anti-carbohydrate B cell repertoire is comprised of a collection of private clonotypes, shaped by antigen selection and affinity maturation, which converge onto multiple discrete reactivities toward carbohydrate antigens.