B Cell Competition for Restricted T Cell Help Suppresses Rare-Epitope Responses

The immune system responds preferentially to particular antigenic-epitopes contained within complex immunogens, such as proteins or microbes. This poorly understood phenomenon, termed ‘‘immunodominance,’’ remains an obstacle to achieving polyvalent immune responses against multiple anti-genic-epitopes through vaccination. We observed profound suppression in the hapten-specific antibody response in mice immunized with hapten-protein conjugate, mixed with an excess of protein, relative to that in mice immunized with hapten-protein alone. The suppression was robust (100-fold and 10-fold with a 10- or 2-fold excess of protein, respectively), stable over a 6-log range in antigen dose, observed within 10 days of vaccination, and resistant to boosting and adjuvants. Furthermore, there were reduced frequencies of antigen-specific germinal-center B cells and long-lived bone-marrow plasma cells. The mechanism of this ‘‘antigen-competition’’ was mediated largely by early access to T-helper cells. These results offer mechanistic in-sights into B cell competition during an immune response and suggest vaccination strategies against HIV, influenza, and dengue.