Intranasal booster drives class switching and homing of memory B cells for mucosal IgA response
Si Chen, Zhengyuan Zhang, Zihan Lin, Li Yin, Lishan Ning, Wenming Liu, Qian Wang, Chenchen Yang, Bo Feng, Ying Feng, Yongping Wang, Hengchun Li, Ping He, Huan Liang, Yichu Liu, Zhixia Li, Bo Liu, Yang Li, Diana Boraschi, Linbing Qu, Xuefeng Niu, Nanshan Zhong, Pingchao Li, Ling Chen
Si Chen, Zhengyuan Zhang, Zihan Lin, Li Yin, Lishan Ning, Wenming Liu, Qian Wang, Chenchen Yang, Bo Feng, Ying Feng, Yongping Wang, Hengchun Li, Ping He, Huan Liang, Yichu Liu, Zhixia Li, Bo Liu, Yang Li, Diana Boraschi, Linbing Qu, Xuefeng Niu, Nanshan Zhong, Pingchao Li, Ling Chen
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Research Article Immunology Infectious disease Public Health

Intranasal booster drives class switching and homing of memory B cells for mucosal IgA response

Abstract

Mucosal secretory IgA (sIgA) plays a central role in protecting against the invasion of respiratory pathogen via the upper respiratory tract. To understand how intranasal booster induces mucosal sIgA response in humans, we first used liquid chromatography–tandem mass spectrometry for peptide identification of immunoglobulin (MS Ig-seq) and single-cell B cell receptor sequencing (scBCR-seq) to identify 42 mucosal spike-specific sIgA monoclonal antibodies (mAbs) after intranasal booster. These mucosal sIgA mAbs exhibited enhanced neutralization up to 100-fold against SARS-CoV-2 variants compared with their monomeric IgG and IgA isotypes. Deep sequencing and longitudinal analysis of B cell receptor repertoires revealed that intranasal booster restimulates memory B cells primed by intramuscular vaccination to undergo IgA class switching, somatic hypermutation, and clonal expansion. Single-cell RNA-seq (scRNA-seq) revealed that intranasal booster upregulated the expression of mucosal homing receptors in spike-specific IgA-expressing B cells. This increase coincided with a transient increase of cytokines and chemokines that facilitate B cell recruitment in the nasal mucosa. Our findings demonstrate that intranasal booster can be an effective strategy for inducing upper respiratory mucosal sIgA and establishing mucosal immune protection.

Authors

Si Chen, Zhengyuan Zhang, Zihan Lin, Li Yin, Lishan Ning, Wenming Liu, Qian Wang, Chenchen Yang, Bo Feng, Ying Feng, Yongping Wang, Hengchun Li, Ping He, Huan Liang, Yichu Liu, Zhixia Li, Bo Liu, Yang Li, Diana Boraschi, Linbing Qu, Xuefeng Niu, Nanshan Zhong, Pingchao Li, Ling Chen

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Figure 4

ScRNA-seq of circulating B cells on day 10 and day 30 after intranasal booster.

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ScRNA-seq of circulating B cells on day 10 and day 30 after intranasal b...
(A and B) The t-SNE plot shows the cell clustering of 16,923 immune cells at 2 time points (A) and specific B cell types (B). The time points of cell clustering are separated according to color, with red representing day 10 and blue representing day 30 (A). Red represents plasmablasts, green represents memory B cells, gray represents naive B cells, and yellow represents exhausted B cells (B). (C) Pie charts depicting the relative proportions of IgA+ (red), IgG+ (blue), and IgM+ (gray) cells in plasmablast and memory B cell populations at day 10 and day 30 post-immunization. (D–F) The t-SNE plots show expression levels of genes ITGA4 (left panel) and ITGB1 (right panel) (D), CCR10 (E), and J CHAIN (F) in B cells on days 10 and 30 after intranasal vaccination. Color intensity represents the level of expression. (G–I) Violin plots showing transcription expression levels of α4β1 (G), CCR10 (H), and J CHAIN (I) in specific B cell types on day 10. Statistical significance was determined using the wilcoxon test, ****P < 0.0001. (J and K) Pie charts depicting the relative proportions of IgA+ (red), IgG+ (blue), and IgM+ (gray) cells in α4β1+ (J) and CCR10+ (K) plasmablast populations on day 10. (L) B cells expressing the same clonotypes as the 45 nasal mucosal mAbs in day 10 and day 30 single B cell sequencing data. Clonotypes 719-3, -4, -17, -30, -33, -39, and -43 were present in the IgA isotype (left panel), while clonotypes 719-3, -4, -11, and -45 were present in the IgG isotype (right panel).