Division of Infectious Diseases, Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, USA.
David H. Smith Center for Vaccine Biology and Immunology, Department of Microbiology and Immunology, University of Rochester Medical Center, Rochester, New York, USA.
J Virol. 2019 Apr 3;93(8). doi: 10.1128/JVI.00169-19. Print 2019 Apr 15.
Memory B cells (MBCs) are key determinants of the B cell response to influenza virus infection and vaccination, but the effect of different forms of influenza antigen exposure on MBC populations has received little attention. We analyzed peripheral blood mononuclear cells and plasma collected following human H3N2 influenza infection to investigate the relationship between hemagglutinin-specific antibody production and changes in the size and character of hemagglutinin-reactive MBC populations. Infection produced increased concentrations of plasma IgG reactive to the H3 head of the infecting virus, to the conserved stalk, and to a broad chronological range of H3s consistent with original antigenic sin responses. H3-reactive IgG MBC expansion after infection included reactivity to head and stalk domains. Notably, expansion of H3 head-reactive MBC populations was particularly broad and reflected original antigenic sin patterns of IgG production. Findings also suggest that early-life H3N2 infection "imprints" for strong H3 stalk-specific MBC expansion. Despite the breadth of MBC expansion, the MBC response included an increase in affinity for the H3 head of the infecting virus. Overall, our findings indicate that H3-reactive MBC expansion following H3N2 infection is consistent with maintenance of response patterns established early in life, but nevertheless includes MBC adaptation to the infecting virus. Rapid and vigorous virus-specific antibody responses to influenza virus infection and vaccination result from activation of preexisting virus-specific memory B cells (MBCs). Understanding the effects of different forms of influenza virus exposure on MBC populations is therefore an important guide to the development of effective immunization strategies. We demonstrate that exposure to the influenza hemagglutinin via natural infection enhances broad protection through expansion of hemagglutinin-reactive MBC populations that recognize head and stalk regions of the molecule. Notably, we show that hemagglutinin-reactive MBC expansion reflects imprinting by early-life infection and that this might apply to stalk-reactive, as well as to head-reactive, MBCs. Our findings provide experimental support for the role of MBCs in maintaining imprinting effects and suggest a mechanism by which imprinting might confer heterosubtypic protection against avian influenza viruses. It will be important to compare our findings to the situation after influenza vaccination.
记忆 B 细胞（MBC）是流感病毒感染和疫苗接种后 B 细胞反应的关键决定因素，但不同形式的流感抗原暴露对 MBC 群体的影响却很少受到关注。我们分析了人类 H3N2 流感感染后采集的外周血单核细胞和血浆，以研究血凝素特异性抗体产生与血凝素反应性 MBC 群体大小和特征变化之间的关系。感染导致血浆中对感染病毒的 H3 头部、保守茎部以及与原始抗原性罪反应一致的广泛 H3 时间范围内的 IgG 反应性增加。感染后 H3 反应性 IgG MBC 的扩增包括对头和茎部结构域的反应性。值得注意的是，H3 头部反应性 MBC 群体的扩增特别广泛，并反映了 IgG 产生的原始抗原性罪模式。研究结果还表明，婴幼儿时期的 H3N2 感染“印记”了强烈的 H3 茎特异性 MBC 扩增。尽管 MBC 的扩增范围很广，但 MBC 的反应包括对感染病毒 H3 头部的亲和力增加。总的来说，我们的研究结果表明，H3N2 感染后 H3 反应性 MBC 的扩增与生命早期建立的反应模式的维持一致，但仍包括 MBC 对感染病毒的适应。快速和有力的流感病毒特异性抗体反应流感病毒感染和疫苗接种的结果是由于激活了预先存在的病毒特异性记忆 B 细胞（MBC）。因此，了解不同形式的流感病毒暴露对 MBC 群体的影响是制定有效免疫策略的重要指南。我们证明，通过自然感染暴露于流感血凝素可通过扩展识别分子的头部和茎部区域的血凝素反应性 MBC 群体来增强广泛的保护作用。值得注意的是，我们表明，血凝素反应性 MBC 的扩增反映了婴幼儿时期感染的“印记”，并且这种印记可能适用于茎反应性以及头部反应性 MBC。我们的研究结果为 MBC 在维持印记效应中的作用提供了实验支持，并提出了一种印记可能赋予对禽流感病毒异源保护的机制。将我们的研究结果与流感疫苗接种后的情况进行比较将是很重要的。
