Genes regulating M cell differentiation

描述（由申请人提供）：我们正在研究粘膜M细胞的发育和功能及其在免疫监视中的作用。我们的目标是确定参与粘膜 M 细胞发育和功能的基因和机制。通过确定 M 细胞生物学中的关键步骤和机制，我们将开始确定它们在粘膜免疫反应中的特定作用及其介导粘膜耐受性和与共生微生物平衡的能力。我们在这些研究中的工作假设是，特定的 TNF 超家族和 TNF 受体超家族基因以及 Jagged-1 的协调表达介导特定 M 细胞发育和功能的细胞相互作用。我们将研究 M 细胞发育的两个主要步骤，这是我们对 CD137 缺陷小鼠的研究所定义的。第一步是来自干细胞的 M 细胞谱系祖细胞的定型，这部分依赖于淋巴毒素受体和 TNFa 受体的配体。已建立的 M 细胞表达 Jagged-1 也可能抑制相邻肠上皮细胞产生 M 细胞。第二步，M 细胞的功能成熟，似乎取决于 M 细胞和基底外侧袋 B 淋巴细胞之间的相互作用。在这里，CD137 (TNFRSF9) 及其配体 CD137L 可能是这种相互作用中的重要信号对。有两个具体目标检验我们假设的这些组成部分：(1) Jagged-1/Notch 相互作用如何调节 M 细胞谱系定型和发育？ (2) 调节 M 细胞基底外侧袋形成和 M 细胞功能发育的特定 CD137/CD137L 细胞相互作用是什么？ 肠粘膜中M细胞稳态数量的调节是一个动态过程，该过程取决于隐窝干细胞、肠上皮和淋巴细胞亚群之间的活跃相互作用。这一过程在派尔氏集结、孤立淋巴滤泡和绒毛 M 细胞之间并行进行，并且会因肠道感染和炎症（例如炎症性肠病）而形成。因此，存在一个反馈回路，其中腔内微生物的 M 细胞转胞吞作用诱导粘膜免疫激活，进而驱动新 M 细胞的产生。我们的研究将提供有关这一过程的积极和消极调节因素的重要细节。

DESCRIPTION (provided by applicant): We are studying the development and function of mucosal M cells and their role in immune surveillance. Our goal is to define the genes and mechanisms involved in the development and function of mucosal M cells. By identifying the critical steps and mechanisms in M cell biology, we will begin to establish their specific role in the mucosal immune response and its ability to mediate mucosal tolerance and the balance with commensal microbes. Our Working Hypothesis in these studies is that specific TNF Superfamily and TNF Receptor Superfamily genes along with coordinated expression of Jagged-1 mediate cellular interactions that specify M cell development and function. We will study two main steps in M cell development, defined by our studies on CD137- deficient mice. The first step is the commitment of M cell lineage progenitors from stem cells, which is dependent in part on ligands for the lymphotoxin ¿ receptors and the TNFa receptors. Expression of Jagged-1 by the established M cells may also inhibit generation of M cells from adjacent enterocytes. The second step, functional maturation of M cells, appears to be dependent on interactions between M cells and basolateral pocket B lymphocytes. Here, CD137 (TNFRSF9) and its ligand CD137L, may be an important signaling pair in this interaction. Two specific aims examine these components of our hypothesis: (1) How is M cell lineage commitment and development regulated by Jagged-1/Notch interactions? (2) What are the specific CD137/CD137L cellular interactions regulating M cell basolateral pocket formation and M cell functional development? Regulation of the steady state numbers of M cells in the intestinal mucosa is a dynamic process, and the process depends on an active interplay between crypt stem cells, intestinal epithelium, and lymphocyte subpopulations. This process works in parallel among Peyer's patch, Isolated Lymphoid Follicles, and Villus M cells, and will be shaped by intestinal infection and inflammation (e.g., in Inflammatory Bowel Disease). Thus, a feedback loop exists where M cell transcytosis of lumenal microbes induces mucosal immune activation, which in turn drives production of new M cells. Our studies will provide important details on both the positive and negative regulators of this process.