Genes regulating M cell differentiation

描述(申请人提供)：我们正在研究粘膜M细胞的发育和功能，以及它们在免疫监测中的作用。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和与共生微生物的平衡的能力。我们在这些研究中的工作假设是，特定的肿瘤坏死因子超家族和肿瘤坏死因子受体超家族基因以及Jagge-1的协调表达介导了指定M细胞发育和功能的细胞相互作用。通过对CD137缺陷小鼠的研究，我们将研究M细胞发育的两个主要步骤。第一步是来自干细胞的M细胞祖细胞的承诺，这在一定程度上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Jagge-1也可能抑制相邻肠细胞产生M细胞。第二步，M细胞的功能成熟，似乎依赖于M细胞和基底外侧袋B淋巴细胞之间的相互作用。在此，CD137(TNFRSF9)及其配体CD137L可能是这种相互作用中的重要信号对。两个特定的目标检验了我们假设的这些组成部分：(1)Jagge-1/Notch相互作用如何调节M细胞的谱系承诺和发育？(2)调控M细胞基外侧囊袋形成和M细胞功能发育的特定CD137/CD137L细胞相互作用是什么？肠粘膜M细胞稳态数量的调节是一个动态的过程，这个过程依赖于隐窝干细胞、肠上皮细胞和淋巴细胞亚群之间的活跃相互作用。这一过程在Peyer氏斑、分离的淋巴滤泡和绒毛M细胞之间并行工作，并将受到肠道感染和炎症的影响(例如，在炎症性肠病中)。因此，存在一个反馈回路，腔内微生物的M细胞跨细胞作用诱导粘膜免疫激活，进而驱动新M细胞的产生。我们的研究将提供关于这一过程的积极和消极调控因素的重要细节。

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.