Malaria exposure drives both cognate and bystander human B cells to adopt an atypical phenotype

Atypical memory B cells (aMBCs) are found in elevated numbers in individuals exposed to malaria. A key question is whether malaria induces aMBCs as a result of exposure to Ag, or non‐Ag‐specific mechanisms. We identified Plasmodium and bystander tetanus toxoid (TT) specific B cells in individuals from areas of previous and persistent exposure to malaria using tetramers. Malaria‐specific B cells were more likely to be aMBCs than TT‐specific B cells. However, TT‐specific B cells from individuals with continuous exposure to malaria were more likely to be aMBCs than TT‐specific B cells in individuals from areas where transmission has ceased. Finally, sequences of BCRs specific for a blood stage malaria‐Ag were more highly mutated than sequences from TT‐specific BCRs and under strong negative selection, indicative of ongoing antigenic pressure. Our data suggest both persistent Ag exposure and the inflammatory environment shape the B‐cell response to malaria and bystander Ags. We investigated antigen specificity of aMBC and classical MBC (cMBC) of adults living in two culturally similar villages, but while one village currently has endemic exposure, malaria transmission disappeared in the other village over 10 years before this study. We found more tetanus‐ and malaria‐specific cMBC in the previously exposed than in the persistently exposed adults. Unexpectedly, tetanus‐specific B cells were more likely to be aMBC in persistently exposed than in previously exposed adults .