Epithelia Associated Dendritic Cells: Phenotype and Function

上皮相关树突状细胞：表型和功能

• 批准号: 7897598
• 负责人: Rodney D Newberry
• 金额: $ 19万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7897598
• 关键词: Animals; Antigen-Presenting Cells; Antigens; Apoptotic; Biological Assay; Cell Maturation; Cell physiology; Cell surface; Cells; Characteristics; Chemotaxis; Conditioned Culture Media; Cues; Cytokeratin; DNA; Dendrites; Dendritic Cells; Diet; Electron Microscopy; Enteral; Environment; Epithelial; Epithelial Cells; Epithelium; Flow Cytometry; Goals; High Pressure Liquid Chromatography; Homing; Human; Immune; Immune response; Immunoglobulin A; Immunoglobulin Class Switching; In Vitro; Infection; Infection prevention; Inflammatory; Intestines; Knowledge; Lamina Propria; Link; Location; Lymphocyte; Mediating; Mesentery; Microscopy; Modeling; Molecular; Morphology; Mus; Phase; Phenotype; Play; Population; Positioning Attribute; Production; Property; Role; Sampling; Seminal; Signal Transduction; Small Intestines; Source; Stimulus; T-Lymphocyte; Techniques; Time; Toll-like receptors; Transmission Electron Microscopy; Vitamin A; Vitamins; Work; carboxylesterase; cell population study; chemokine receptor; cytokine; dietary requirement; imprint; intestinal epithelium; lymph nodes; lymphocyte proliferation; pathogen; prevent; receptor function; response; uptake

DESCRIPTION (provided by applicant): Dendritic cells (DCs) are potent antigen presenting cells that play an essential role initiating and guiding immune responses toward intestinal pathogens and non-pathogens. Recent studies using microscopy techniques demonstrated that the intestine contains a population of DCs that are uniquely positioned at the interface of the host with the environment. These DCs extend dendrites into the intestinal lumen to sample and respond to stimuli and because of their physical location these DCs have great potential to influence immune responses. Despite these seminal observations, studies directly assessing this DC population are lacking. The function of these cells is largely inferred from studies of related DC populations, and from studies of in vitro derived DCs treated with epithelial cell conditioned media. Furthermore the phenotypic diversity of this DC population is almost completely unexplored. In this proposal we will define the phenotypic and functional diversity of epithelium associated dendritic cells (EA-DC) from the mouse and human small intestine. The overarching hypothesis of this proposal is that intestinal EA-DC include two subtypes of DCs with dichotomous phenotypes and functions, inflammatory DCs and tolerogenic DCs. These DCs migrate from the lamina propria (LP) to become closely associated with the epithelium in response to pathogenic or non- pathogenic signals respectively, sample lumenal stimuli, including dietary vitamin A, and subsequently migrate to mesenteric lymph nodes (MLN) to initiate vitamin A dependent mucosal adaptive immune responses. In specific aim 1 we will define the phenotypic and functional diversity of the murine and human EA-DC population. These studies will evaluate this population of cells with flow cytometry to define the EA-DC subtypes and examine these cells for the expression of toll like receptors and chemokine receptors. The morphology of these EA-DC subtypes will be evaluated with electron microscopy. The function of these DC subtypes will be investigated by evaluating the ability of these cells to imprint gut homing of lymphocytes, induce IgA class switch, and stimulate and differentiate T-lymphocytes. The physical location of the EA-DC subtypes will be evaluated in models of non-pathogenic and pathogenic infections. In specific aim 2 we will define the role of dietary vitamin A in establishing the EA-DC niche and in EA-DC function by evaluating the EA-DC subtypes for the expression of specialized molecular machinery for the uptake and storage of dietary vitamin A. We will evaluate the role of dietary source of vitamin A for mucosal specific functions of the EA-DC, and we will evaluate a role for dietary vitamin A in altering DC phenotype to occupy the EA niche. Dendritic cells are the most powerful immune cells for starting and guiding the character of immune responses, thus these cells play important roles in defending against infections and in preventing unwanted harmful immune responses. The intestine contains unique populations of dendritic cells that we know very little about. This study will increase our knowledge about how these dendritic cells work to protect us from intestinal infections and prevent unwanted harmful immune responses.

描述（由申请人提供）：树突状细胞（DC）是有效的抗原呈现细胞，它们起着对肠道病原体和非pathogens的免疫反应起着至关重要的作用。使用显微镜技术的最新研究表明，肠中包含一群DC，这些DC位于宿主与环境的界面上。这些DC将树突扩展到肠腔中以采样并响应刺激，并且由于其物理位置，这些DC具有影响免疫反应的巨大潜力。尽管进行了这些开创性的观察，但仍缺乏直接评估DC人群的研究。这些细胞的功能在很大程度上是根据对DC种群的研究以及用上皮细胞条件培养基处理的体外衍生DC的研究来推断的。此外，该DC种群的表型多样性几乎完全没有探索。在此提案中，我们将定义与小鼠和人类小肠相关的树突状细胞（EA-DC）的表型和功能多样性。该提议的总体假设是肠道EA-DC包括两个具有二分法表型和功能的DC亚型，炎症DC和耐受性DC。 These DCs migrate from the lamina propria (LP) to become closely associated with the epithelium in response to pathogenic or non- pathogenic signals respectively, sample lumenal stimuli, including dietary vitamin A, and subsequently migrate to mesenteric lymph nodes (MLN) to initiate vitamin A dependent mucosal adaptive immune responses.在特定目标1中，我们将定义鼠和人类EA-DC人群的表型和功能多样性。这些研究将评估具有流式细胞术的细胞群，以定义EA-DC亚型，并检查这些细胞是否表达了像受体和趋化因子受体一样的Toll。这些EA-DC亚型的形态将通过电子显微镜评估。这些DC亚型的功能将通过评估这些细胞的能力构成淋巴细胞的肠道含量，诱导IgA类转换并刺激和区分T淋巴细胞的能力来研究。 EA-DC亚型的物理位置将在非致病和致病感染模型中评估。在特定目标2中，我们将通过评估EA-DC亚型来确定饮食中维生素A在建立EA-DC的作用和EA-DC功能中的作用表型占据Ea -eaine。树突状细胞是启动和指导免疫反应特征的最强大的免疫细胞，因此这些细胞在防御感染和预防不必要的有害免疫反应方面起着重要作用。肠道包含我们对树突状细胞的独特种群，我们对此知之甚少。这项研究将增加我们对这些树突状细胞如何工作以保护我们免受肠道感染并防止有害的有害免疫反应的知识。