Systemic-to-mucosal trafficking of memory B cells contributes to humoral immunity in the upper respiratory tract

Systemic vaccination induces serum antibodies and circulating memory B cells but provides limited protection in the upper respiratory tract, where many respiratory pathogens initiate infection. How systemic memory B cells contribute to mucosal immunity remains unclear. Using multiparametric flow cytometry, single-cell RNA and V(D)J sequencing, and functional analyses of paired blood and nasal/oropharyngeal samples, we characterized human B cells across systemic and mucosal compartments. Swab-derived B cells transcriptionally overlap with circulating activated memory B cells while exhibiting distinct features of activation, tissue retention, and spontaneous IgA/IgG secretion. Approximately 6% of mucosal B-cell clones were shared with blood, indicating systemic-mucosal connectivity. Both infection and vaccination expanded two circulating antigen-specific activated memory B cells subsets, whereas antigen-specific B cells accumulated in the upper respiratory tract only following local inflammation. The finding that B-cell recruitment is reactive rather than preemptive may explain the limited efficacy of parenteral vaccines and provides a rationale for developing integrated systemic-mucosal vaccination strategies.