IMMUNODOMINANCE WITH PROGENITOR B-CELL DIVERSITY IN THE NEUTRALIZING ANTIBODY REPERTOIRE TO INFLUENZA INFECTION

We report striking immunodominance in the neutralizing antibody respon ses of major histocompatibility complex congenic mice to natural infec tion with influenza virus (H3N2 subtype), as deduced by sequencing the hemagglutinin (HA) genes of monoclonal antibody (mAb)-selected mutant viruses. A majority of mAb, established from individual BALB/c (H-2(d )) mice, select mutant viruses containing the same single amino acid s ubstitution in the membrane distal ectodomain, HA1 198 A-->E, whereas changes at either HA1 158 G-->E or HA1 198 A-->E are selected for by m Ab from BALB.K (H-2(k)) donors. The structural basis for immunodominan ce, and potential diversity of progenitor B cells, was investigated by sequence analysis of H and L chain gene rearrangements in mAb specifi c for HA1 158 or HA1 198. No correlation was found between antibody sp ecificity and V-H or V-L gene usage, and a minimum of three to six pro genitor cells contributed to the individual's repertoire for a single antigenic site. However, in a further analysis of the HA1 158-specific antibody response of CBA/Ca (H-2(k)) donors, there was highly restric ted light chain gene usage. Focusing of the immune repertoire to limit ed regions of the HA molecule during a primary viral infection may be a significant factor in immune pressure for antigenic variation, parti cularly since there is no evident restriction in the antibody response to immunization.