Antigenic epitopes differ in their immunogenicity. Yewdell and colleagues show that B cell and antibody responses to influenza A virus infection display reproducible dynamic immunodominance hierarchies to viral hemagglutinin epitopes. Immunodominance (ID) defines the hierarchical immune response to competing antigens in complex immunogens. Little is known regarding B cell and antibody ID despite its importance in immunity to viruses and other pathogens. We show that B cells and serum antibodies from inbred mice demonstrate a reproducible ID hierarchy to the five major antigenic sites in the influenza A virus hemagglutinin globular domain. The hierarchy changed as the immune response progressed, and it was dependent on antigen formulation and delivery. Passive antibody transfer and sequential infection experiments demonstrated 'original antigenic suppression', a phenomenon in which antibodies suppress memory responses to the priming antigenic site. Our study provides a template for attaining deeper understanding of antibody ID to viruses and other complex immunogens.

Influenza A virus (IAV) imposes a significant socioeconomic burden on humanity. Vaccination is effective in only 60% of individuals, even under optimal circumstances. The difficulty stems from the remarkable ability of IAV to evade existing immunity. IAV's error prone polymerase enables the rapid antigenic evolution of the two virion surface glycoproteins, neuraminidase and hemagglutinin (HA). Since the most potent antibodies (Abs) at neutralizing viral infectivity are directed the head of the HA, amino acid substitutions in this region enable IAV to evade Ab-based immunity. Here, we review recent progress in understanding how immunodominance, the tendency of the immune system to respond to foreign immunogens in a hierarchical manner, shapes IAV evolution.

B cell responses are critical for antiviral immunity. However, a comprehensive picture of antigen-specific B cell differentiation, clonal proliferation, and dynamics in different organs after infection is lacking. Here, by combining single-cell RNA and B cell receptor (BCR) sequencing of antigen-specific cells in lymph nodes, spleen, and lungs after influenza infection in mice, we identify several germinal center (GC) B cell subpopulations and organ-specific differences that persist over the course of the response. We discover transcriptional differences between memory cells in lungs and lymphoid organs and organ-restricted clonal expansion. Remarkably, we find significant clonal overlap between GC-derived memory and plasma cells. By combining BCR-mutational analyses with monoclonal antibody (mAb) expression and affinity measurements, we find that memory B cells are highly diverse and can be selected from both low- and high-affinity precursors. By linking antigen recognition with transcriptional programming, clonal proliferation, and differentiation, these finding provide important advances in our understanding of antiviral immunity.