An extensive analysis was made of receptor specificity and gene usage in the neutralising antibody (mAb) and Class II-restricted T cell responses to influenza haemagglutinin (HA) following natural infection of MHC (H-2k or H-2d) congenic mice with X31 virus (H3N2 subtype). Despite the diversity of available antigenic sites on the HA1 subunit, there was striking immunodominance in the mAb response as deduced by sequencing the HA genes of escape mutants and the corresponding antibody H and L chain gene rearrangements. Similarly, Class II restricted T cell responses of individual donors focused on a single antigenic site, or immunodominant peptide; and PCR sequence analysis of T cell receptor (αβ) gene usage indicated that T cell memory was derived from a single progenitor cell. Focusing of the immune repertoire to limited regions of the HA molecule during a primary viral infection may be a significant factor in immune pressure for antigenic variation.