Elucidating the function of the transcription factor Bhlhe41 during B-1a cell development and in imprinting of B-1a cell self-renewal properties

阐明转录因子 Bhlhe41 在 B-1a 细胞发育过程中和 B-1a 细胞自我更新特性印记中的功能

• 批准号: 419105595
• 负责人: Dr. Josefine Dunst
• 金额: --
• 依托单位: Department of Medicine, Solna
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2019
• 资助国家: 德国
• 起止时间: 2018-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/419105595?language=en
• 关键词: Elucidating; function; transcription; factor; Bhlhe41

B-1a cells are a subset of innate-like B lymphocytes which can contribute to the first line of defense upon pathogen encounter as well as to clearing cellular debris to maintain tissue homeostasis. B-1a cells are primarily generated during fetal and neonatal life and are less efficiently replenished by adult bone marrow, and therefore they maintain their numbers throughout the lifetime of an organism by self-renewal. Although cytokine receptor signaling and certain metabolic requirements are pertinent to B-1a cell self-renewal, the precise molecular mechanisms underlying the ability of B-1a cells to self-renew remain elusive. Moreover, while an instructive role of B cell receptor signaling has been implicated in the diversion toward the B-1a cell lineage, B-1a cell development is still poorly understood. Recently, the transcription factor Bhlhe41 was identified as a key regulator of B-1a cell development and self-renewal. Published results obtained with Bhlhe41 germline-deficient mice suggested that Bhlhe41 plays two temporally distinct roles in B-1a cells – first controlling their development early in ontogeny and later regulating the unique self-renewal properties of mature B-1a cells. However, our preliminary data obtained by conditional deletion of Bhlhe41 during early and late B-1a cell development challenge this model and indicate that Bhlhe41 may be largely dispensable in mature B-1a cells. Moreover, these results also suggest that the unique self-renewal properties of mature B-1a cells are ‘imprinted’ by Bhlhe41 in a narrow time window early in B-1a cell differentiation. Therefore, the ultimate goal of this research project is to elucidate the function of Bhlhe41 during B-1a cell development and in imprinting of B-1a cell self-renewal properties. To accomplish this goal, I will pursue the following specific aims: First, I will thoroughly characterize the B-1a cell compartment upon conditional deletion of Bhlhe41 early and late in B-1a cell development. Second, I will decipher the cellular and molecular function of Bhlhe41 during early B-1a lymphopoiesis, as well as in a system of inducible B-1a cell differentiation recently developed by Prof. Rajewsky’s lab. Finally, as an additional direction, I will also aim to use Bhlhe41 as a molecular marker to identify a so far elusive population of human B 1a cells. Together, the results obtained within this research project will not only be valuable in advancing our understanding of the humoral immune system of mice and men, but also provide significant insights into molecular mechanisms of self-renewal.

B-1a细胞是先天样B淋巴细胞的一个亚群，它可以在遇到病原体时起到第一道防线的作用，并清除细胞碎片以维持组织稳态。B-1a细胞主要在胎儿和新生儿时期产生，成年骨髓的补充效率较低，因此它们通过自我更新在生物体的整个生命周期中保持其数量。尽管细胞因子受体信号传导和某些代谢需求与B-1a细胞自我更新有关，但B-1a细胞自我更新能力的精确分子机制仍然难以捉摸。此外，虽然B细胞受体信号传导的指导性作用涉及B-1a细胞谱系的转移，但B-1a细胞的发育仍然知之甚少。最近，转录因子Bhlhe41被确定为B-1a细胞发育和自我更新的关键调节因子。从Bhlhe41种系缺陷小鼠中获得的已发表的结果表明，Bhlhe41在B-1a细胞中起着两种不同的作用——首先在个体发育早期控制它们的发育，然后调节成熟B-1a细胞独特的自我更新特性。然而，我们通过在B-1a细胞发育的早期和晚期条件缺失Bhlhe41获得的初步数据挑战了这一模型，并表明Bhlhe41在成熟的B-1a细胞中可能在很大程度上是不必要的。此外，这些结果还表明成熟B-1a细胞独特的自我更新特性是在B-1a细胞分化早期的一个狭窄的时间窗口内被Bhlhe41“印记”的。因此，本研究项目的最终目标是阐明Bhlhe41在B-1a细胞发育过程中的功能，以及印迹B-1a细胞自我更新特性。为了实现这一目标，我将追求以下具体目标：首先，我将在B-1a细胞发育的早期和后期条件删除Bhlhe41时彻底表征B-1a细胞区室。其次，我将破译Bhlhe41在早期B-1a淋巴形成过程中的细胞和分子功能，以及最近由Rajewsky教授实验室开发的诱导B-1a细胞分化系统。最后，作为一个额外的方向，我也将致力于使用Bhlhe41作为分子标记来识别迄今为止难以捉摸的人类b1a细胞群体。总之，在这个研究项目中获得的结果不仅对我们对小鼠和男性体液免疫系统的理解有价值，而且还为自我更新的分子机制提供了重要的见解。