Mapping the germinal center and memory B cell landscape to complex antigens

将生发中心和记忆 B 细胞景观映射到复杂抗原

基本信息

项目摘要

ABSTRACT Vaccines are one of the most successful public health interventions over the past century. Of the 28 licensed vaccines, nearly all of them work by induction of protective antibodies capable of neutralizing the pathogen. However, our understanding of the cellular dynamics of immune responses to vaccines, particularly the biology surrounding B cell competition within germinal centers (GC) and memory B cell biology to complex vaccine antigens, has remained limited. This lack of fundamental understanding of these biological processes may be a contributor to the failure to develop an effective HIV vaccine, despite nearly 30 years of research. The fact that a small population of HIV+ individuals develop broadly neutralizing antibodies (bnAbs) gives renewed hope that an HIV vaccine is indeed possible. Recent work has found that many HIV negative healthy human donors have VRC01-class precursor B cells. However, work from these studies revealed that these potential bnAb precursor B cells are found at an unusually rare frequency, suggesting that following immunization these B cells would be outcompeted by more frequent non-neutralizing B cells. To answer immunological questions surrounding this problem, I developed a model system utilizing mice containing human genes for the germline- reverted VRC01 bnAb (VRC01gHL), together with teams from the labs of Dr. David Nemazee and Dr. William Schief. Through this B cell transfer model, we found that antigen affinity, avidity, and precursor frequency all played interdependent roles in competitive success of rare VRC01gHL B cells in GCs. Critically, we found that rare VRC01gHL B cells with physiological affinities could be primed to successfully compete within GCs and form memory. In this K99/R00 proposal I will build on these findings. I will explore how precursor frequency and affinity affect the balanced output of memory B cell and long lived plasma cells from GCs, and how Tfh help can modulate these processes. I will assess how these parameters affect recall and competitive success of VRC01gHL memory B cells. Moreover, I will investigate if different metabolic pathways are involved in successful recruitment of memory VRC01gHL B cells to and within secondary GCs. I will further my training by developing a co-T cell transfer method to specifically study the impact of different Tfh pathways in competitive success of VRC01gHL B cells. The K99 phase will be conducted in the laboratory of Dr. Shane Crotty at the La Jolla Institute (LJI). Dr. Crotty is an ideal mentor as he has a highly successful history in studying vaccine biology, particularly T follicular helper (Tfh) biology. He has also explored this biology related to HIV vaccines. I will additionally receive formal training in antibody characterization through coursework and further develop real world training in immunogen production and design in the laboratory of Dr. William Schief as a visiting scientist. During the R00 phase, I will take my experimental models with me and investigate multiple parameters affecting memory cell biology. These will include studying the roles of circulating antibody, memory Tfh, and “metabolic memory” of B cells.
摘要 疫苗是过去世纪最成功的公共卫生干预措施之一。在28个获得许可的 几乎所有的疫苗都是通过诱导能够中和病原体的保护性抗体来起作用的。 然而,我们对疫苗免疫反应的细胞动力学的理解,特别是生物学, 周围B细胞在生发中心(GC)内的竞争和记忆B细胞生物学对复合疫苗 抗原,仍然有限。对这些生物学过程缺乏基本的了解可能是一个 尽管进行了近30年的研究,但仍未能开发出有效的艾滋病毒疫苗。的事实 一小部分HIV阳性个体产生了广泛中和抗体(bnAb),这给人们带来了新的希望, 艾滋病疫苗确实是可能的。最近的研究发现,许多HIV阴性的健康人类捐赠者 VRC 01类前体B细胞。然而,这些研究表明,这些潜在的bnAb 前体B细胞以异常罕见的频率被发现,这表明免疫后这些B细胞 细胞将被更频繁的非中和性B细胞竞争。来回答免疫学问题 围绕这个问题,我开发了一个模型系统,利用含有人类生殖细胞基因的小鼠- 与来自大卫内马齐博士和威廉博士实验室的团队一起, 我的天通过这种B细胞转移模型,我们发现抗原亲和力、亲合力和前体频率都与细胞的增殖和分化有关。 在GC中罕见的VRC 01 gHL B细胞的竞争成功中起相互依赖的作用。关键是,我们发现 具有生理亲和性的稀有VRC 01 gHL B细胞可被引发以成功地在GC内竞争, 形式记忆在本K99/R 00提案中,我将以这些发现为基础。我将探索前兆频率 和亲和力影响GCs的记忆B细胞和长寿浆细胞的平衡输出,以及Tfh如何影响GCs的记忆B细胞和长寿浆细胞的平衡输出。 帮助可以调节这些过程。我将评估这些参数如何影响召回和竞争成功 VRC 01 gHL记忆B细胞。此外,我将研究不同的代谢途径是否参与了 成功地将记忆性VRC 01 gHL B细胞募集到次级GC中。我会继续训练 开发一种co-T细胞转移方法,专门研究不同Tfh途径对竞争性T细胞转移的影响。 VRC 01 gHL B细胞的成功。K99阶段将在洛杉矶的Shane Crotty博士的实验室进行。 Jolla Institute(LJI).克罗蒂博士是一个理想的导师,因为他在研究疫苗方面有着非常成功的历史。 生物学,特别是T滤泡辅助细胞(Tfh)生物学。他还探索了与艾滋病毒疫苗相关的生物学。我 此外,还将通过课程接受抗体表征方面的正式培训,并进一步发展 真实的世界的培训免疫原生产和设计在威廉博士的实验室作为访问 科学家在R 00阶段,我将带着我的实验模型, 影响记忆细胞生物学的参数。这些研究将包括研究循环抗体,记忆, Tfh和B细胞的“代谢记忆”。

项目成果

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Robert Koehler Abbott其他文献

Robert Koehler Abbott的其他文献

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{{ truncateString('Robert Koehler Abbott', 18)}}的其他基金

Revealing the Biophysics of the Germinal Center Microenvironment
揭示生发中心微环境的生物物理学
  • 批准号:
    10543399
  • 财政年份:
    2021
  • 资助金额:
    $ 25.1万
  • 项目类别:

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