SREBP signaling regulates lung resident memory B cell metabolism to sustain allergic memory

IgE drives allergic airway disease, yet the mechanisms sustaining IgE memory remain incompletely understood. Using a murine model of allergy, we identified CCR6? CD69? lung-resident memory B cells (BRM) that persist after sensitization and expand rapidly upon allergen re-exposure, generating allergen-specific IgG1 and IgE. Transcriptomic analysis revealed that BRM adopt a distinct lipid metabolic program regulated by sterol regulatory element-binding protein (SREBP) signaling. Conditional deletion of this pathway revealed stage-specific roles: it is essential for GC-derived BRM formation, dispensable for maintenance, yet critical during memory recall to support BRM expansion, plasma cell differentiation, and local antibody production. Loss of SREBP signaling during memory recall impaired fatty acid metabolism, protein synthesis and effector differentiation in BRM, while also reducing plasma cell metabolic fitness, resulting in diminished IgG1 and IgE production. These findings identify a lung BRM subset as a key driver of pathogenic antibody responses and establish SREBP signaling as a stage-specific regulator of BRM, highlighting sterol pathways as potential therapeutic targets for allergic disease. Overall design: Wild-type and SCAP cKO mice were intranallly treated with house dust mite (HDM) extract to establish airway allergy, and rechallenged with the same allergen six weeks later to induce memory recall response. For SCAP cKO, SCAP was deleted before memory recall. CCR6? CD69?, CCR6? CD69? lung resident csMBCs and circulating csMBCs from were sorted for bulk RNA-seq.