Germinal-center derived, somatically hypermutated ­Plasmodium-specific IgM+ memory B cells are optimally responsive to a secondary blood stage malaria infection

Abstract

Abstract Humoral immunity consists of pre-existing antibodies expressed by long-lived plasma cells and rapidly reactive memory B cells (MBCs). Secondary responses by MBCs traditionally are thought to involve the production of class-switched, high affinity antibodies that can neutralize an invading pathogen if pre-existing antibody concentrations are not sufficient to control infection. In infections with high pathogen loads, like blood stage malaria, MBC induction may therefore be critical and has been correlated with protection. What types of MBCs are important for mediating this protection remains unknown. Recent studies have expanded upon conventional MBC paradigms and phenotypically and functionally heterogeneous MBCs have been described in mice and humans. To gain insight into the types of MBCs that form and function during primary and secondary Plasmodium infection, we developed a novel B cell tetramer against the Plasmodium blood stage protein, Merozoite Surface Protein 1 (MSP1). In a murine model of Plasmodium infection three distinct MSP1-specific MBCs form: an IgG+, IgD+ and IgM+population, which are all maintained for long periods of time. These three subsets are phenotypically and genetically distinct, have different developmental histories and respond to a secondary iRBC challenge in unique ways. Remarkably, somatically hypermutated MSP1-specific IgM+ MBCs outcompete IgG+ MBCs early during a secondary challenge resulting in the expansion of newly formed plasmablasts and increased levels of serum MSP1-specific IgM antibodies. As a result, this study highlights a previously unrecognized role for IgM+ MBCs during an infection and should be considered a target population when developing an anti-malarial vaccine.