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

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 IgA is a predominant immunoglobulin isotype at mucosal surfaces whose epithelial cells express polymeric Ig receptor (pIgR) capable of transporting dimeric IgA to the lumen. While 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 (BRM) and plasmablasts and plasma cells. IgA-secreting cell establishment within the lung required CXCR3. Notably, an intranasally administered protein-based vaccine also led to the establishment of IgA-secreting cells in lung, but not when given intramuscularly or intraperitoneally. Finally, 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.

黏膜表面分泌的抗体可通过中和病原体并促进其在入侵部位清除，在免疫防御中发挥不可或缺的核心作用。分泌型免疫球蛋白A（Secretory IgA）是黏膜表面的主要免疫球蛋白亚型，其上皮细胞表达多聚免疫球蛋白受体（polymeric Ig receptor, pIgR），可将二聚体IgA转运至管腔。尽管IgA在肠黏膜中的作用已得到广泛研究，但负责分泌IgA以保护宿主抵御下呼吸道病原体的细胞类型仍不甚明确。
本研究借助流感病毒感染小鼠模型，证实鼻内而非全身性免疫可诱导支气管肺泡腔局部IgA分泌。通过单细胞RNA测序，我们在呼吸道黏膜中发现了表达IgA的异质性细胞群，包括组织驻留记忆B细胞（tissue-resident memory B cells, BRM）、浆母细胞与浆细胞。肺内IgA分泌细胞的建立依赖CXCR3（CXC趋化因子受体3）。值得注意的是，鼻内给药的蛋白疫苗同样可诱导肺内IgA分泌细胞形成，而肌内或腹腔内接种则无此效果。最后，相较于单独的循环抗体，局部IgA分泌与更优异的抗同源及异源病毒二次攻毒保护作用相关。
本研究结果为基于组织驻留IgA分泌B细胞的肺部保护性免疫建立机制提供了关键见解，并为旨在引发针对呼吸道病毒感染的高效免疫保护的疫苗研发策略提供了参考。