Increasingly divergent responses to infection in mice suggest B cell evolution is not constrained by germline-encoded specificities

AbstractAntibodies result from the competition of B cell lineages evolving under selection for improved antigen recognition, a process known as affinity maturation. High-affinity antibodies to pathogens such as HIV, influenza, and SARS-CoV-2 are frequently reported to arise from B cells whose receptors, the precursors to antibodies, are encoded by particular immunoglobulin alleles. This raises the possibility that the presence of particular germline alleles in the B cell repertoire is a major determinant of the quality of the antibody response. Alternatively, initial differences in germline alleles’ propensities to form high-affinity receptors might be overcome by chance events during affinity maturation. We first show how this can happen in simulations: even when fitness differences between germline alleles lead to similar allele usage across individuals early on, allele usage becomes increasingly dissimilar over time. We next find that mice experimentally infected with influenza virus demonstrate the same pattern of divergence in the weeks following infection. We investigated whether affinity maturation might nonetheless strongly select for particular amino acid motifs across diverse genetic backgrounds, but we found no evidence of convergence to similar CDR3 sequences or amino acid substitutions. These results suggest germline-encoded specificities might enable fast recognition of specific antigens early in the response, but diverse evolutionary routes to high affinity limit the genetic predictability of responses to infection and vaccination in the long term.