Polarizing T Cell Responses in vivo With Dendritic Cells

使用树突状细胞极化体内 T 细胞反应

• 批准号: 9321597
• 负责人: BALI PULENDRAN
• 金额: --
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-09-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9321597
• 关键词: Ablation; Amino Acids; Anti-inflammatory; Antigen Presentation; Autoantigens; Autoimmune Diseases; Autoimmunity; Autophagocytosis; Cells; Data; Dendritic Cells; Epithelial Cells; Equilibrium; Extracellular Signal Regulated Kinases; Failure; Goals; Immune Tolerance; Immune response; Immune system; Immunity; Impairment; Individual; Inflammasome; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-10; Intestines; Knockout Mice; MEKs; Mediating; Microbe; Mitochondria; Molecular; Mucosal Immunity; Mus; Pathology; Pathway interactions; Phosphotransferases; Predisposition; Production; Property; Reactive Oxygen Species; Regulatory T-Lymphocyte; Research; Role; Signal Pathway; Signal Transduction; Starvation; T cell response; TLR2 gene; Testing; Virus; Work; autoreactivity; beta catenin; biological adaptation to stress; detection of nutrient; imprint; in vivo; insight; member; novel; novel therapeutic intervention; programs; response; retinoic acid 4-hydroxylase; sensor; transcription factor

Emerging evidence suggests a central role for dendritic cells (DCs) in inducing immune tolerance. Our recent research has provided critical new insights into the molecular mechanisms that “program” DCs to induce tolerogenic responses. In particular, we have observed an unappreciated intersection between the ancient nutrient-sensing pathway, involving the amino acid sensing molecule GCN2, and control of inflammation in the gut. Given the central role of GCN2 as a sensor of amino acid starvation, we explored its’ potential role in the intestine, and observed its remarkable effects on modulating the functions of intestinal DCs and epithelial cells to control inflammation in the gut. In this context the goal of the research proposed here is to determine the mechanisms by which GCN2 and this stress response pathway regulate gut inflammation. Aim 1: To determine the mechanism by which the GCN2-eIF2α pathway regulates intestinal immunity and inflammation. Our preliminary data demonstrates that GCN2-/- mice display enhanced susceptibility to intestinal inflammation and strikingly enhanced Th17 responses. Here we will explore the effects of conditional ablation of GCN2 expression in DCs versus intestinal epithelial cells, and whether these effects are dependent on down the downstream kinase eIF2α. Aim 2: To determine the cause and consequence of excess reactive oxygen species (ROS) production in GCN2 deficient mice. Our preliminary data show that GCN2-/- mice have enhanced intestinal inflammation and elevated levels of ROS in gut DCs and epithelial cells. In this aim we propose to determine the cause and consequence of excess ROS production in the GCN2-/- mice. Aim 3: To determine the mechanism by which GCN2 suppresses inflammasome activation. Finally, our preliminary data demonstrates increased inflammasome activation in gut DCs and epithelial cells in GCN2-/- mice. In this aim, we will determine whether this inflammasome activation is essential for enhanced intestinal inflammation and Th17 responses. The successful completion of these aims will provide new mechanistic insights into how this stress response pathway controls intestinal inflammation, and provide new therapeutic strategies against autoimmunity.

新兴证据表明，树突状细胞（DC）在诱导的免疫耐受性中起着核心作用。我们的最新消息 研究为“编程” DC诱导的分子机制提供了关键的新见解。 耐受反应。特别是，我们观察到古老的 营养感应途径，涉及氨基酸传感分子GCN2，并控制炎症 肠道。鉴于GCN2作为氨基酸饥饿的传感器的核心作用，我们探索了其在 肠，并观察到其对调节肠道和上皮的功能的显着影响 细胞控制肠道注射。在这种情况下，这里提出的研究的目的是确定 GCN2和该应力反应途径调节肠道注射的机制。 目标1：确定GCN2-EIF2α途径调节肠道免疫的机制 和炎症。我们的初步数据表明GCN2 - / - 小鼠显示出增强的敏感性 肠炎和明显增强的Th17反应。在这里，我们将探索 DCS与肠上皮细胞中GCN2表达的条件消融，以及这些影响是否影响 取决于下游激酶EIF2α。 目标2：确定过量活性氧（ROS）的原因和结果 在GCN2缺乏小鼠中产生。我们的初步数据表明，GCN2 - / - 小鼠具有增强的肠道 肠道DC和上皮细胞中ROS的炎症和升高。在此目标中，我们建议确定 GCN2 - / - 小鼠中ROS过多的原因和后果。 目标3：确定GCN2抑制炎症体激活的机制。最后， 我们的初步数据表明，肠道DC和上皮细胞中的炎性体激活增加 GCN2 - / - 小鼠。在此目标中，我们将确定这种炎性体激活是否对增强至关重要 肠炎和Th17反应。 这些目标的成功完成将为这种压力反应提供新的机械见解 途径控制肠道感染，并为自身免疫提供新的治疗策略。