Holly A. Fryer, Catherine Pitt, Hannah R. Frost, Nitika Kandhari, Sean Byars, Pailene S. Lim, Rhiannon L. Fettes, Reece M. Lovett, Trang T. Nguyen, Kaneka Chheng, Natalie Caltabiano, Alana L. Whitcombe, Julianne Hamelink, Dean Andrew, Gareth Lloyd, Brian Wilson-Boyd, Nicola Slee, Jodie Ballantine, Sarju Vasani, Kathryn Girling, Liam Gubbels, Eric Levi, Karen Davies, Stuart G. Tangye, Jonathan Noonan, Nicole J. Moreland, Isaak Quast, Marcus J Robinson, S.W. Scally, Melanie R. Neeland, Shivanthan Shanthikumar, Joshua Osowicki, David M. Tarlinton, Andrew C. Steer, Michelle J. Boyle, Danika L. Hill
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.