Modulation of B cell responses by previously elicited antibodies

Abstract

The ability to generate humoral responses is a fundamental feature of adaptive immune system, and forms the basis of vaccine efficacy. Upon initial exposure to an antigen, B cells, the cellular source of antibodies, are recruited to form germinal centers (GCs). Here, they undergo affinity maturation prior to differentiation into memory B cells and antibody secreting plasma cells. The effectiveness of this process is in part determined by the pool of B cell clones that are recruited during the early stages of the response. Greater diversity within the GC B cell population increases chances of producing antibodies binding neutralizing epitopes. However, the rules that govern B cell recruitment into the GC are not fully understood. Here, we show that antibodies elicited during primary immune response can modulate the participation of cognate naïve B cells during secondary challenges, thereby directly altering the quality and composition of the responses that follow repeated immune challenge. We find that high-affinity antigen specific antibodies are sufficient to exclude naïve antigen-specific B cells during secondary challenges, and we can restrict corresponding B cell subsets from participating in GC responses through administration of antibodies in an affinity, concentration and epitope-dependent manner. Additionally we demonstrate that administering immunogen-specific monoclonal antibodies can restrict their corresponding naïve B cell populations from entering the GC in context of challenges with multiple immunogens, potentially providing an opportunity tune diversity of these responses. Finally we present a novel single-cell sequencing method intended to deconvolute the antigen-specificity and clonal diversity of GC responses raised through concomitant administration of immunogen, in turn, proving new insights into the complexity of the GC environment. Overall, these findings have major implications for vaccine design, particularly those relying on the administration of consecutive doses of immunogen, and may need to be taken into consideration during future vaccine development.