Journal
SCIENCE
Volume 360, Issue 6385, Pages 223-226Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aao3859
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Funding
- National Health and Medical Research Council [1016953, 1113904, 1108800, 585490, 1081858]
- Australian Research Council [160104915, 140103465]
- Bill and Patricia Ritchie Foundation
- MRC [MC_U105178804] Funding Source: UKRI
- National Health and Medical Research Council of Australia [1108800, 1081858] Funding Source: NHMRC
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Antibodies have the specificity to differentiate foreign antigens that mimic self antigens, but it remains unclear how such specificity is acquired. In a mouse model, 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 detected rapid selection for mutations that decrease self affinity and slower selection for epistatic mutations that specifically increase foreign affinity. Crystal structures revealed that these mutations exploited subtle topological differences to achieve 5000-fold preferential binding to foreign over self epitopes. Resolution of antigenic mimicry drove the optimal affinity maturation trajectory, highlighting the value of retaining self-reactive clones as substrates for protective antibody responses.
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