Exponential proofreading: the kinetic mechanism of B cell immune response and cross-protection

Protective B-cell immunity relies on two complementary layers: circulating antibodies that neutralize pathogens and memory B cells that provide rapid recall responses upon reinfection. While empirical correlations between antibody titer and protection are established, the dynamics of in-vivo memory immune response has remained unclear. Here we show that B cell response involves exponential proofreading, a new mechanism with affinity-graded initiation of clonal proliferation. This mechanism generates responding repertoires characterized by power law correlations between clone size and affinity with specific differences between primary and memory response. We validate these predictions in empirical data of B cell responses to acute infections and vaccinations in mice. The model further predicts two important features of cross-protection: the depth, defined as the relative potency of a memory response compared to a primary response to the same antigen, and the breadth, which quantifies the decay of potency against an evolving antigen. We test these predictions from data of human cross-immunity against evolving influenza strains. Together, our analysis shows how infection kinetics and the architecture of the immune system conspire to generate potent responses to pathogens.