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

我研究计划的长期目标是阐明控制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，因为几十年的研究已经提供了广泛的细胞，分子和遗传事件的特征，这些事件调节淋巴细胞的发育和功能，免疫的主要效应器。有两种主要的淋巴细胞系，T细胞和B细胞，分别介导细胞和体液免疫反应。有趣的是，在淋巴细胞发育过程中会产生两种不同功能的T细胞和B细胞。“传统”淋巴细胞表达针对罕见微生物抗原的克隆多样抗原受体，这些抗原受体在数周内触发它们分化为免疫效应细胞或记忆细胞。相比之下，先天样淋巴细胞对常见微生物成分的特异性抗原受体较少，抗原暴露会促使它们在数小时内分化为抗微生物效应细胞，而不是数天。因此，先天样淋巴细胞是“天然的”效应/记忆细胞，在常规淋巴细胞介导适应性免疫应答之前提供早期免疫保护。本研究的重点是先天样边缘区（MZ） B细胞，它表达对常见细菌壁部分的特异性受体，并能迅速分化为抗体分泌细胞。有趣的是，MZ B细胞的产生和维持，而不是传统的B细胞，需要激活Notch2受体。然而，Notch2信号在这些过程中的具体功能尚不清楚。因此，我们的目标是确定Notch2激活促进先天样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.