Harnessing Age-Associated B cells for a Universal Influenza Vaccine for the Aged

摘要： 利用年龄相关的B细胞为老年人接种通用流感疫苗。随着年龄的增长， 从幼稚的CD4T细胞产生T滤泡助手，从滤泡B细胞产生生发中心B细胞， 都是产生高亲和力抗体(Ab)所必需的，都会高度受损。最新版本 老年人的流感疫苗在诱导这些关键反应方面并不有效。因此，老年人， 尽管已经为生命早期遇到的病原体提供了抗体保护，但它们对新的 病毒株(如流感)和新出现的病原体(如大流行性流感、新冠肺炎)。我们 描述了一群不寻常的分泌抗体的B细胞的产生，这种细胞发展成活的流感 老年小鼠的感染。我们发现它们是由最近描述的“年龄相关的B细胞”的刺激产生的 幼稚的sIgD+表型的“细胞”(ABC)。在老年人中，产生这些流感诱导的ABC(IABC) 独立于CD4T细胞的帮助，但严格依赖于病原体相关的“危险”信号的刺激 因此，它们在老年感染的小鼠中产生得很好。值得注意的是，ABC是主要的幼稚B细胞 对衰老小鼠的反应。 在这里，我们将确定免疫球蛋白ABC对流感感染做出反应并产生抗体分泌细胞的潜力 (ABSC)再循环或组织驻留的效应器IABC。我们将确定它们是否会产生B 细胞记忆，包括静止记忆和长寿抗体分泌细胞，如果在较低的 呼吸道(肺)和上呼吸道(URT)：鼻组织和鼻相关淋巴组织- NALT)，以及脾和骨髓。我们将确定ABC衍生的效应器和记忆的贡献 亚群及其在这些不同部位产生的抗体，以保护免受再次感染.我们会问你要多久- 活着的是位于不同地点的记忆细胞。我们会比较活的流感病毒，整体灭活的能力 病毒和mRNA-LNP HA疫苗产生循环和组织驻留效应和记忆亚群 并诱导保护性免疫。这些结果将使我们对这种新的年龄相关免疫有新的认识。 途径，并为我们提供了重要的新见解，即利用老年ABC反应是否可以提供 在老年人中提供卓越的保护。它将提供一般疫苗策略可能是什么的迹象 需要为老年人接种ABC疫苗。这些发现可能导致一种更通用的疫苗，它可以 为目前高度脆弱的老年人提供强有力的保护。

ABSTRACT: Harnessing Age-Associated B Cells for a Universal Influenza Vaccine for the Aged. With age, the generation of T follicular helpers from naive CD4 T cells, and germinal center B cells from follicular B cells, that are both needed for the generation of high affinity antibody (Ab), become highly compromised. Most current vaccines for influenza in the elderly are not effective at inducing these critical responses. Thus, the elderly, though protected by Ab already in place for pathogens encountered earlier in life, are highly susceptible to new strains of virus (e.g. influenza) and newly emerged pathogens (e.g. pandemic influenzas, COVID-19). We described the generation of an unusual population of Ab-secreting B cells that developed to live influenza infection in aged mice. We found they were derived from stimulation of recently described "age-associated B cells" (ABC) of a naïve sIgD+ phenotype. In the aged, these influenza-induced ABC (iABC) are generated independently of CD4 T cell help, but strictly depend on stimulation by pathogen-associated "danger" signals and thus they are generated well in aged infected mice. Notably, ABC are the predominant naïve B cells that respond in aged mice. Here we will determine the potential of IgD ABC to respond to influenza infection and generate Ab-secreting cells (AbSC) effector iABC that are either recirculating or are tissue resident. We will determine if they give rise to B cell memory, both resting memory and long-lived Ab-secreting cells, and if these are found in the lower respiratory tract (lung) and upper respiratory tract (URT):nasal tissues and nasal associated lymphoid tissue- NALT), as well as the spleen and BM. We will determine the contribution of ABC-derived effector and memory subsets and the Ab they produce in these the different sites to protection from reinfection. We will ask how long- lived are the memory cells in distinct sites. We will compare the ability of live influenza virus, whole inactivated virus, and mRNA-LNP HA vaccine to generate the recirculating and tissue resident effector and memory subsets and to induce protective immunity. These results will give us new insights into this novel age-associated immune pathway and give us important new insights into whether harnessing the aged ABC response can provide superior protection in the aged. It will provide indications of what general vaccine strategies are likely to be needed to immunize the ABC in the elderly. These findings could lead to a more Universal vaccines that can provide robust protection to the elderly, who are currently highly vulnerable.