Intranasal priming induces local lung-resident B cell populations that secrete protective mucosal antiviral IgA

Flu defense via lung-resident IgA+ memory B cells
Secretory IgA antibody is known to be a key effector molecule in establishing effective antiviral immunity in the lungs, but the specific cell types producing this mucosal IgA and their physical locations are unclear. Oh et al. analyzed pulmonary IgA-secreting cells in mice after prior influenza infection or after intranasal immunization with an adjuvanted recombinant neuraminidase flu vaccine. Both replicating flu virus and the protein-based vaccine induced enhanced antiviral immunity and IgA production when administered intranasally rather than by alternate parenteral routes. The IgA responses were mediated through a combination of lung-resident memory B cells, plasmablasts, and plasma cells.

These findings add to the growing evidence that mucosal vaccination strategies show enhanced efficacy in establishing frontline mucosal immunity against respiratory pathogens.


Abstract
Antibodies secreted at the mucosal surface play an integral role in immune defense by serving to neutralize the pathogen and promote its elimination at the site of entry. Secretory immunoglobulin A (IgA) is a predominant Ig isotype at mucosal surfaces whose epithelial cells express polymeric Ig receptor capable of transporting dimeric IgA to the lumen. Although the role of IgA in intestinal mucosa has been extensively studied, the cell types responsible for secreting the IgA that protects the host against pathogens in the lower respiratory tract are less clear. Here, using a mouse model of influenza virus infection, we demonstrate that intranasal, but not systemic, immunization induces local IgA secretion in the bronchoalveolar space. Using single-cell RNA sequencing, we found a heterogeneous population of IgA-expressing cells within the respiratory mucosa, including tissue-resident memory B cells, plasmablasts, and plasma cells. IgA-secreting cell establishment within the lung required CXCR3. An intranasally administered protein-based vaccine also led to the establishment of IgA-secreting cells in the lung, but not when given intramuscularly or intraperitoneally. Last, local IgA secretion correlated with superior protection against secondary challenge with homologous and heterologous virus infection than circulating antibodies alone.

These results provide key insights into establishment of protective immunity in the lung based on tissue-resident IgA-secreting B cells and inform vaccine strategies designed to elicit highly effective immune protection against respiratory virus infections.

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