A Blast from the Past – Recall of Memory B Cells to Fight Future Threats

Abstract

The adaptive arm of immune response includes the formation of antigen-specific memory B cells (MBCs) and antibody-secreting cells (ASCs) following the activation of naive B cells. While the majority of ASCs have a finite lifespan and only a few home to the bone marrow to become long-lived plasma cells (LLPCs), MBCs persist in the circulation and remain detectable years after the initial exposure. Therefore, MBCs could influence future trajectories of B cell responses when an individual is reinfected with antigenically-related pathogens. Early observation in the 1960s provided evidence that responses to influenza A virus (IAV) in adults included preferential production of antibodies to the priming immunogens instead of responding to the boosting immunogens, thus earning its moniker, the original antigenic sin (OAS). OAS suggests that the recalled antibodies have limited antiviral capacities against the boosting immunogens by likely targeting the conserved non-neutralizing epitopes that the priming and boosting immunogens share. Several decades past, the molecular and cellular mechanisms of OAS remain the subject of intense scrutiny. Multiple studies have shown OAS-like phenotype in multiple viral contexts. However, most of these studies are limited to analyzing serum antibodies. Therefore, we sought to elucidate roles of preexisting cross-reactive MBC populations in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and IAV vaccination. To enumerate antigen-specific MBCs from PBMCs, we stimulated MBCs using TLR7/8 agonist to induce their differentiation into MBC-derived Ab-secreting cells (MASCs). We evaluated the size of the MBC populations using ELISpot readout and measured supernatants containing antibodies produced by MASCs through binding assays. The magnitude of the MBC response was then analyzed together with circulating antigen-specific serum antibodies and ASCs to gain a comprehensive picture of MBC responses. From our SARS-CoV-2 studies, we identified strong signatures of MBC recall response by measuring responses against spike proteins from related ꞵ-coronaviruses. Moreover, our data hinted towards rapid adaptation of MBCs towards features present on the spike of SARS-CoV-2 of the recalled MBC populations. This informed how preexisting antigen-specific MBCs are recalled to participate against infection and could be used to guide better vaccine designs.