Germinal center antibody mutation trajectories are determined by rapid self/foreign discrimination

Burnett DL, Langley DB, Schofield P, Hermes J, Chan TD, Jackson J, Bourne K, Brink R, Christ D and Goodnow C

Garvan Institute of Medical Research.

Antibodies have exquisite specificity to differentiate foreign antigens that mimic “self”, but it remains unclear how such specificity is acquired. We generated B-cells displaying an antibody that cross-reacts with two related protein antigens expressed on self versus foreign cells. B-cell anergy was imposed by self antigen but reversed upon challenge with high-density foreign antigen, leading to germinal center recruitment and antibody gene hypermutation. Single-cell analysis revealed rapid selection for mutations that decrease self affinity and slower selection for epistatic mutations that specifically increase foreign affinity. Crystal structures revealed the mutations exploited subtle topological differences to achieve 5,000-fold preferential binding to foreign targets over self epitopes. Strikingly, resolution of antigenic mimicry drove the optimal affinity maturation trajectory, highlighting the value of retaining self-reactive clones as substrates for protective antibody responses.