Pathogenic IgE-fated memory B cell responses retain functional plasticity

Abstract Long-lived immunoglobulin (Ig) E responses against innocuous environmental and dietary antigens (Ags) are maintained by an IgG1-dominant memory B cell (MBC) compartment primed for IL-4 responsiveness. The plasticity of the MBC compartment destined for IgE class switch recombination (CSR), however, remains poorly understood. In this work, we report a critical IL-4/IL-13 dependency for the pathogenic IgE fate of type 2-polarized MBCs. Initiating a recall response in the absence of IL-4/IL-13 signaling diminished the type 2 MBC phenotype in mice and humans and, in mice, permitted the emergence of long-lived Ag-specific IgG2c + MBCs. The divergence to a type 1-like response was dependent on IFN-γ signaling and arose from both unswitched and class-switched Ag-specific B cells in vivo . This reprogrammed fate was sustained even beyond therapeutic intervention, revealing fundamental insight into the plasticity of the allergen-specific MBC response. One Sentence Summary B cell responses to allergens can be reprogrammed away from a pathogenic fate through IL-4/IL-13 signaling blockade.