Polarizing T Cell Responses in vivo With Dendritic Cells

新的证据表明树突状细胞（DC）在诱导免疫耐受中发挥着核心作用。我们最近的 研究为“编程”树突状细胞诱导的分子机制提供了重要的新见解 耐受性反应。特别是，我们观察到古代和古代之间存在未被重视的交叉点。 营养感应途径，涉及氨基酸感应分子 GCN2，以及炎症的控制 肠道。鉴于 GCN2 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： 观察其对肠道 DC 和上皮细胞功能的显着调节作用 细胞控制肠道炎症。在此背景下，本文提出的研究目标是确定 GCN2 和应激反应通路调节肠道炎症的机制。 目的1：确定GCN2-eIF2α通路调节肠道免疫的机制 和炎症。我们的初步数据表明 GCN2-/- 小鼠表现出增强的易感性 肠道炎症和 Th17 反应显着增强。下面我们就来探讨一下效果 DC 与肠上皮细胞中 GCN2 表达的条件性消融，以及这些影响是否 依赖于下游激酶 eIF2α。 目标 2：确定活性氧 (ROS) 过量的原因和后果 GCN2 缺陷小鼠中的生产。我们的初步数据表明 GCN2-/- 小鼠的肠道功能增强 肠道 DC 和上皮细胞中的炎症和 ROS 水平升高。为此，我们建议确定 GCN2-/- 小鼠中 ROS 产生过多的原因和后果。 目标 3：确定 GCN2 抑制炎症小体激活的机制。最后， 我们的初步数据表明肠道 DC 和上皮细胞中炎症小体的激活增加 GCN2-/- 小鼠。为此，我们将确定这种炎性体激活是否对于增强 肠道炎症和 Th17 反应。 这些目标的成功完成将为了解这种压力反应如何提供新的机制见解 途径控制肠道炎症，并提供针对自身免疫的新治疗策略。

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.