Polarizing T Cell Responses in vivo With Dendritic Cells

新出现的证据表明，树突状细胞（DC）在诱导免疫耐受中发挥着重要作用。我们最近 研究已经提供了关键的新见解的分子机制，“程序”DC诱导 致耐受性反应。特别是，我们观察到一个未被欣赏的交叉点， 包括氨基酸传感分子GCN 2在内的营养物传感途径， 内脏鉴于GCN 2作为氨基酸饥饿传感器的核心作用，我们探索了其在以下方面的潜在作用： 并观察其对肠道DC和上皮细胞功能的调节作用 细胞来控制肠道炎症。在这种情况下，这里提出的研究目标是确定 GCN 2和这种应激反应途径调节肠道炎症的机制。 目的1：探讨GCN 2-eIF 2 α通路调节肠道免疫的机制 和炎症。我们的初步数据表明，GCN 2-/-小鼠显示出增强的易感性， 肠道炎症和显著增强的Th 17应答。在这里，我们将探讨的影响 条件性消融DC与肠上皮细胞中GCN 2的表达，以及这些效应是否 依赖于下游激酶eIF 2 α。 目的2：确定过量活性氧（ROS）的原因和后果 在GCN 2缺陷小鼠中的生产。我们的初步数据显示，GCN 2-/-小鼠的肠道功能增强， 炎症和肠DC和上皮细胞中ROS水平升高。为此，我们建议确定 GCN 2-/-小鼠中过量ROS产生的原因和后果。 目的3：确定GCN 2抑制炎性小体激活的机制。最后， 我们的初步数据表明，在肠上皮细胞和树突状细胞中炎性小体活化增加， GCN 2-/-小鼠。在这个目标中，我们将确定这种炎性小体激活是否是增强炎症反应的必要条件。 肠道炎症和Th 17应答。 这些目标的成功完成将为这种压力反应如何提供新的机制见解 途径控制肠道炎症，并提供新的治疗策略，以对抗自身免疫。

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.