Pathogenic IgE-fated memory B cell responses retain functional plasticity

Long-lived immunoglobulin E (IgE) responses against innocuous environmental and dietary antigens (Ags) are maintained by an IgG1-dominant memory B cell (MBC) compartment primed for interleukin-4 (IL-4) responsiveness. The plasticity of the MBC compartment destined for IgE class switch recombination remains poorly understood. In this work, we report critical IL-4 and IL-13 dependency for the pathogenic IgE fate of type 2-polarized MBCs in allergy. Initiation of a recall response in the absence of IL-4 and IL-13 signaling diminished the type 2 MBC phenotype in mice and humans. This permitted the emergence of long-lived Ag-specific IgG2c⁺ MBCs in mice. The divergence to a type 1-like response was dependent on interferon-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 insights into the plasticity of the allergen-specific recall response.