Functions of Notch Signaling in Marginal Zone B Cell Differentiation and Homeostasis

我的研究计划的长期目标是阐明管理细胞谱系承诺和分化的分子机制。我们使用小鼠免疫系统作为我们的实验模型，因为数十年的研究已经提供了调节淋巴细胞（免疫的主要效应物）的发育和功能的细胞、分子和遗传事件的广泛表征。存在两种主要的淋巴细胞谱系，T和B细胞，其分别介导细胞与体液免疫应答。有趣的是，在淋巴细胞发育过程中产生了两种不同功能类型的T细胞和B细胞。“常规”淋巴细胞表达对稀有微生物抗原特异性的克隆多样性抗原受体，这在数周的过程中触发它们分化为免疫效应细胞或记忆细胞。相比之下，先天样淋巴细胞具有对常见微生物组分特异性的较少多样性的抗原受体库，并且抗原暴露驱使它们在数小时而不是数天内分化成抗微生物效应细胞。因此，先天样淋巴细胞是“天然的”效应/记忆细胞，其在常规淋巴细胞可以介导适应性免疫应答之前提供早期免疫保护。该提议集中于先天样边缘区（MZ）B细胞，其表达对常见细菌壁部分特异性的受体，并且可以快速分化成抗体分泌细胞。有趣的是，MZ B细胞而非常规B细胞的产生和维持需要Notch 2受体的活化。然而，Notch 2信号在这些过程中的具体功能是未知的。因此，我们的目标是确定Notch 2激活促进先天性MZ B细胞分化和稳态的机制。

The long-term goal of my research program is to elucidate molecular mechanisms that govern cellular lineage commitment and differentiation. We use the murine immune system as our experimental model, since decades of study have provided extensive characterization of cellular, molecular and genetic events that regulate the development and function of lymphocytes, the major effectors of immunity. There are two major lymphocyte lineages, T and B cells, which mediate cellular versus humoral immune responses, respectively. Interestingly, two different functional classes of both T and B cells are produced during lymphocyte development. 'Conventional' lymphocytes express clonally diverse antigen receptors specific for rare microbial antigens, which trigger their differentiation into immune effector or memory cells over the course of several weeks. In contrast, innate-like lymphocytes have less diverse antigen receptor repertoires specific for common microbial components, and antigen exposure drives their differentiation into anti-microbial effector cells within hours rather than days. Thus, innate-like lymphocytes are "natural" effector/memory cells that provide early immune protection well before conventional lymphocytes can mediate adaptive immune responses. This proposal is focused on innate-like marginal zone (MZ) B cells, which express receptors specific for common bacterial wall moieties, and can rapidly differentiate into antibody-secreting cells. Interestingly, generation and maintenance of MZ B cells, but not conventional B cells, requires activation of the Notch2 receptor. However, the specific functions of Notch2 signaling in these processes are unknown. Therefore, our objective is to define mechanisms by which Notch2 activation promotes differentiation and homeostasis of innate-like MZ B cells.