Allergen-specific memory B cells adopt tissue-imprinted differentiation programs upon recall, with lymphoid-resident MBCs accessing IL-4-rich germinal center microniches formed by Tfh cells to generate IgE-producing plasma cells through a GC-dependent pathway, while lung-resident MBCs follow a GC-independent route that produces predominantly IgG1 responses, thereby establishing anatomical compartmentalization as a regulatory mechanism that restricts pathogenic IgE production to lymphoid organs and prevents inappropriate IgE responses at barrier tissues frequently exposed to environmental antigens.

Immunoglobulin E (IgE) drives allergic disease, yet how memory B cells (MBCs) reactivate to produce IgE, and how tissue localization shapes recall responses, remains unclear. Using mouse models of airborne exposure to house dust mites and Alternaria, we found that allergen sensitization generates lymphoid- and lung-resident MBCs. Upon allergen re-exposure, these populations followed distinct differentiation trajectories: lymph node MBCs engaged a germinal center (GC)-dependent pathway that generated both IgG1⁺ and IgE⁺ plasma cells (PCs), whereas lung MBCs followed a GC-independent route producing mainly IgG1⁺ PCs. GC re-entry granted MBCs access to an IL-4-rich microniche formed by Tfh cells, which was essential for IgE production. Disrupting GC re-entry, IL-4 signaling, or Tfh-derived IL-4 during recall markedly reduced allergen-specific IgE titers. These findings reveal a spatially and cytokine-restricted mechanism that confines IgE memory to lymphoid organs, positioning GC IL-4 microniches as anatomical safeguards against IgE production at barrier sites frequently exposed to environmental antigens.