The Development and Function of Plasmodium-specific memory B cells

记忆B细胞和长寿的浆细胞负责产生中和 能有效清除病原体的抗体。了解这些细胞在体内的功能 因此，对感染的反应以及如何通过接种疫苗来诱导和维持这些反应 对根除构成全球卫生负担的疾病至关重要。疟疾，由疟原虫引起 SPP是一种迫切需要疫苗的全球主要健康负担。五十多年前，它 研究表明，人免疫血清的转移可以中和疟原虫 感染的血液阶段。然而，人们对疟原虫特异的B细胞知之甚少 产生这些抗体是因为研究低频抗原特异性B蛋白的困难 细胞。此外，目前还不清楚最近描述的异质性种群 由蛋白质免疫形式或功能诱导的记忆B细胞亚群 感染。为了阐明不同的MBC亚群在疟疾感染过程中的功能作用，四聚体 在人类和小鼠身上都产生了识别疟原虫特异性的单核细胞。 多参数流式细胞术和单细胞B细胞受体测序结果显示，长- 活的小鼠疟原虫特异的单核细胞由三个群体组成：体细胞 超突变，经典定义的免疫球蛋白+(IgG+)，一种以前未被识别的 体细胞超突变的IgM+(IgMHighIgDlow)单核细胞和未突变的IGD+(IgMlowIgDHigh)单核细胞 人口。令人惊讶的是，疟原虫特异性IgM+抗体主导了对 继发感染。进一步的分析表明，在重新激发时，IgM+单核细胞迅速形成 两个抗体分泌群体：T细胞非依赖性浆细胞和T依赖性IgM+和 免疫球蛋白阳性的浆母细胞。因此，IgM+MBCs是对疟原虫的快速、可塑性的第一反应 再次挑战，并应成为疫苗战略的目标。我们现在准备进一步 鉴定这些和其他疟原虫特异的B细胞群，以确定它们独特的 在人类和相关的小鼠模型中对预防疟疾的贡献。这个 这个应用程序的中心假设是，功能不同的开发还没有 疫苗介导的保护需要记忆B细胞的协同群体 疟原虫。这项提议的目标是确定分子和细胞机制。 导致这些不同的单核细胞亚群的形成，并确定这些细胞是如何 有助于在老鼠和人类身上预防疟疾。这种创新的方法可以 提供研制首个有效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.