The Development and Function of Plasmodium-specific memory B cells

记忆B细胞和长寿浆细胞负责产生中和 能有效消灭病原体的抗体了解这些细胞的功能 因此，对感染的反应以及如何通过疫苗接种诱导和维持这些反应， 这对根除构成全球健康负担的疾病至关重要。疟疾，由疟原虫引起 spp是一个主要的全球健康负担，迫切需要疫苗。五十多年前， 研究表明，转移人免疫血清可以中和疟原虫寄生虫， 感染的血液阶段。然而，关于疟原虫特异性B细胞知之甚少， 由于研究低频率抗原特异性B的困难， 细胞此外，目前还不清楚最近描述的异质性群体是如何形成的。 由蛋白免疫诱导的记忆B细胞（MBC）亚群响应于 感染为了阐明不同MBC亚群在疟疾感染期间的功能作用， 在人类和小鼠中鉴定疟原虫特异性MBC。 多参数流式细胞术和单细胞B细胞受体测序显示，长- 活的鼠疟原虫特异性MBC由三个群体组成：体细胞 高度突变，经典定义的IgG+（IgG+），以前未被识别的人群， 体细胞高突变IgM+（IgMhighIgDlow）MBC和未突变IgD+（IgMlowIgDhigh）MBC 人口令人惊讶的是，疟原虫特异性IgM+抗体主导了对疟疾的早期反应。 继发感染进一步的分析显示，在再激发后，IgM+ MBC迅速形成， 两种抗体分泌群体：T细胞非依赖性浆细胞和T依赖性IgM+， IgG+浆母细胞。因此，IgM+ MBC是对疟原虫的快速、可塑性、第一反应者 再次激发，并应通过疫苗策略进行靶向治疗。我们现在准备进一步 表征这些和其他疟原虫特异性B细胞群体，以确定其独特的 在人类和相关鼠模型中预防疟疾的贡献。的 本申请的中心假设是，功能异质性的发展还 疫苗介导的保护需要记忆B细胞的协同群体， 疟原虫本提案的目标是确定分子和细胞机制 导致这些不同MBC亚群的形成，并确定这些细胞如何 有助于保护小鼠和人类免受疟疾的侵害。这种创新的方法可以 提供研制首个有效的疟疾疫苗所需的信息。

Memory B cells and long-lived plasma cells are responsible for producing neutralizing antibodies that can effectively eliminate a pathogen. Understanding the function of these cells in response to infection and how they can be induced and maintained by vaccination is therefore critical to eradicating diseases that are global health burdens. Malaria, caused by Plasmodium spp, is a major global health burden that is in urgent need of a vaccine. Over fifty years ago it was shown that transfer of human immune serum can neutralize Plasmodium parasites during the blood stage of infection. Little is known however about the Plasmodium-specific B cells that produce these antibodies due to the difficulties of studying low frequency antigen-specific B cells. Additionally, it is not understood how recently described populations of heterogeneous memory B cell (MBC) subsets induced by protein immunization form or function in response to infection. To clarify functional roles for distinct MBC subsets during malaria infection, tetramers were generated that identify Plasmodium-specific MBCs in both humans and mice. Multiparameter flow cytometry and single-cell B cell receptor sequencing revealed that long- lived murine Plasmodium-specific MBCs consisted of three populations: somatically hypermutated, classically defined IgG+ (IgG+), a previously unrecognized population of somatically hypermutated IgM+ (IgMhighIgDlow) MBCs and an unmutated IgD+ (IgMlowIgDhigh) MBC population. Surprisingly, Plasmodium-specific IgM+ antibody dominated the early response to a secondary infection. Further analyses revealed that upon rechallenge, IgM+ MBCs rapidly form two antibody-secreting populations: T cell-independent plasma cells and T-dependent IgM+ and IgG+ plasmablasts. IgM+ MBCs are therefore rapid, plastic, first responders to Plasmodium rechallenge and should be targeted by vaccine strategies. We are now poised to further characterize these and other Plasmodium-specific B cell populations to determine their unique contributions to protection against malaria in both humans and relevant murine models. The central hypothesis of this application is that the development of functionally heterogeneous yet synergistic populations of memory B cells will be required for vaccine-mediated protection to Plasmodium. The goals of this proposal are to identify the molecular and cellular mechanisms that lead to the formation of these distinct MBC subsets and to determine how these cells contribute to protection against malaria in mice and humans. This innovative approach could provide the information required to develop the first effective vaccine against malaria.