Zeb2 drives the formation of CD11c ⁺ atypical B cells to sustain germinal centers that control persistent infection

Abstract

CD11c + atypical B cells (ABCs) are an alternative memory B cell lineage associated with immunization, infection, and autoimmunity. However, the factors that drive the transcriptional program of ABCs have not been identified, and the function of this population remains incompletely understood. Here we identified candidate transcription factors associated with the ABC population based on a human tonsillar B cell single cell dataset. We identified CD11c + B cells in mice with a similar transcriptomic signature to human ABCs, and using an optimized CRISPR-Cas9 knockdown screen, we observed that loss of zinc finger E-box binding homeobox 2 (Zeb2) impaired ABC formation. Furthermore, ZEB2 haplo-insufficient Mowat Wilson syndrome (MWS) patients have decreased circulating ABCs in the blood. In Cd23 Cre/+ Zeb2 fl/fl mice with impaired ABC formation, ABCs were dispensable for efficient humoral responses after Plasmodium sporozoite immunization but were required to control recrudescent blood-stage malaria. Immune phenotyping revealed that ABCs drive optimal T follicular helper (Tfh) cell formation and germinal center (GC) responses and they reside at the red/white pulp border likely permitting better access to pathogen antigens for presentation. Collectively, our study shows that ABC formation is dependent upon Zeb2, and these cells can limit recrudescent infection by sustaining GC reactions.

Differences in phenotype between long-lived memory B cells againstPlasmodium falciparummerozoite antigens and variant surface antigens

“…Gao et al . recently showed that atypical B cells were better at presenting antigen and activating CD4 + T cells than other B cell subsets ( 39 ). In line with these observations, we show that atypical B cell subset 1 (that seems primed for antigen presentation) was enriched for particle-associated CIDRα1-specific B cells over B cells with specificity for soluble antigens MSP1 and AMA1, suggesting that capturing infected erythrocytes and presenting parasite antigens to T cells may be an important function of this atypical B cell subset.…”