Pathogenic IgE-fated B cell memory retains functional plasticity

Long-lived immunoglobulin (Ig) E responses against innocuous environmental and dietary antigens are maintained by an IgG1-dominant memory B cell (MBC) compartment primed for IL-4 responsiveness. In this work, we investigated the plasticity of the MBC compartment fated for IgE class switch recombination upon antigen (Ag) re-exposure. Antibody-mediated IL-4Rα blockade augmented the germinal center response and uncovered an IL-4/IL-13 dependency within the type 2 memory B cell (MBC2) skewed phenotype. In the absence of IL-4/IL-13 signaling during the recall response, a long-lived Ag-specific IgG2c MBC population emerged, shifting the MBC response away from a Th2 phenotype and towards a Th1 phenotype. The emergence of this IgG2 response was dependent on IFN-γ signaling and arose from both unswitched and class-switched Ag-specific B cells in vivo. We further demonstrated that a Th1 adjuvant can redirect the isotypic fate of Th2-polarized class-switched MBCs, suggesting with the correct cues pathogenic MBCs can be functionally reprogrammed. ### Competing Interest Statement JFEK, SW, and MJ receive funding from ALK Abello A/S. All other authors declare that they have no competing interests.