School of Biomedical Sciences, The University of Western Australia, Crawley, WA, Australia.
Division of Immunology, PathWest Laboratory Medicine, Nedlands, WA, Australia.
Front Immunol. 2021 Sep 28;12:738123. doi: 10.3389/fimmu.2021.738123. eCollection 2021.
The diversity of B cell subsets and their contribution to vaccine-induced immunity in humans are not well elucidated but hold important implications for rational vaccine design. Prior studies demonstrate that B cell subsets distinguished by immunoglobulin (Ig) isotype expression exhibit divergent activation-induced fates. Here, the antigen-specific B cell response to tetanus toxoid (TTd) booster vaccination was examined in healthy adults, using a dual-TTd tetramer staining flow cytometry protocol. Unsupervised analyses of the data revealed that prior to vaccination, IgM-expressing CD27 B cells accounted for the majority of TTd-binding B cells. 7 days following vaccination, there was an acute expansion of TTd-binding plasmablasts (PB) predominantly expressing IgG, and a minority expressing IgA or IgM. Frequencies of all PB subsets returned to baseline at days 14 and 21. TTd-binding IgG and IgA memory B cells (MBC) exhibited a steady and delayed maximal expansion compared to PB, peaking in frequencies at day 14. In contrast, the number of TTd-binding IgMIgDCD27 B cells and IgM-only CD27 B cells remain unchanged following vaccination. To examine TTd-binding capacity of IgG MBC and IgMIgDCD27 B cells, surface TTd-tetramer was normalised to expression of the B cell receptor-associated CD79b subunit. CD79b-normalised TTd binding increased in IgG MBC, but remained unchanged in IgMIgDCD27 B cells, and correlated with the functional affinity index of plasma TTd-specific IgG antibodies, following vaccination. Finally, frequencies of activated (PD-1ICOS) circulating follicular helper T cells (cT), particularly of the CXCR3CCR6 cT2 cell phenotype, at their peak expansion, strongly predicted antigen-binding capacity of IgG MBC. These data highlight the phenotypic and functional diversity of the B cell memory compartment, in their temporal kinetics, antigen-binding capacities and association with cT cells, and are important parameters for consideration in assessing vaccine-induced immune responses.
B 细胞亚群的多样性及其对人类疫苗诱导免疫的贡献尚不清楚，但对合理的疫苗设计具有重要意义。先前的研究表明，根据免疫球蛋白（Ig）同种型表达区分的 B 细胞亚群表现出不同的激活诱导命运。在这里，使用双重破伤风类毒素（TTd）四聚体染色流式细胞术方案，研究了健康成年人对破伤风类毒素（TTd）加强疫苗接种的抗原特异性 B 细胞反应。对数据进行无监督分析显示，在接种疫苗之前，表达 IgM 的 CD27 B 细胞占 TTd 结合 B 细胞的大多数。接种疫苗后 7 天，TTd 结合的浆母细胞（PB）发生急性扩增，主要表达 IgG，少数表达 IgA 或 IgM。所有 PB 亚群的频率在第 14 天和第 21 天恢复到基线。与 PB 相比，TTd 结合的 IgG 和 IgA 记忆 B 细胞（MBC）表现出稳定和延迟的最大扩增，在第 14 天达到频率峰值。相比之下，接种疫苗后，TTd 结合的 IgMIgDCD27 B 细胞和 IgM 仅 CD27 B 细胞的数量保持不变。为了检查 IgG MBC 和 IgMIgDCD27 B 细胞对 TTd 的结合能力，将表面 TTd-四聚体与 B 细胞受体相关的 CD79b 亚基的表达归一化。接种疫苗后，IgG MBC 中的 TTd 结合增加，但 IgMIgDCD27 B 细胞中的 TTd 结合保持不变，并且与血浆 TTd 特异性 IgG 抗体的功能亲和力指数相关。最后，在其峰值扩增时，活化的（PD-1ICOS）循环滤泡辅助 T 细胞（cT），特别是 CXCR3CCR6 cT2 细胞表型的频率，强烈预测 IgG MBC 的抗原结合能力。这些数据突出了 B 细胞记忆区室在其时间动力学、抗原结合能力及其与 cT 细胞的关联方面的表型和功能多样性，是评估疫苗诱导免疫反应时需要考虑的重要参数。
