Germinal center interleukin-4 microniches drive tissue divergence of IgE memory B cell responses.

Immunoglobulin E (IgE) drives allergy, 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 generated lymph node (LN)- and lung-resident MBCs. Upon allergen re-exposure, MBCs follow two differentiation trajectories: a germinal center (GC)-dependent pathway, generating IgG1+ and IgE+ plasma cells (PCs) and occurring predominantly in LNs, and a GC-independent pathway, generating mainly IgG1+ PCs and present in both organs. GC re-entry granted MBCs access to an interleukin (IL)-4-rich microniche formed by T follicular helper (Tfh) cells, which was essential for IgE production. Disrupting GC re-entry, IL-4 signaling, or Tfh cell-derived IL-4 during recall markedly reduced allergen-specific IgE. 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.