Polarizing T Cell Responses in vivo With Dendritic Cells

新的证据表明，树突状细胞(DC)在诱导免疫耐受中起着核心作用。我们最近 研究为“编程”DC诱导的分子机制提供了关键的新见解 耐受性反应。特别是，我们观察到一种不为人知的交集，在古代 涉及氨基酸感应分子GCN2的营养感应通路与炎症的控制 我的直觉。鉴于GCN2作为氨基酸饥饿感受器的核心作用，我们探索了它在 肠道，观察其对肠道树突状细胞和上皮细胞功能的调节作用 控制肠道炎症的细胞。在这种情况下，这里提出的研究的目标是确定 GCN2和这个应激反应通路调节肠道炎症的机制。 目的1：探讨GCN2-eIF2α途径调节肠道免疫功能的机制 和炎症。我们的初步数据显示，GCN2-/-小鼠表现出更强的易感性 肠道炎症和显著增强的Th17反应。在这里，我们将探讨 有条件地消融DC相对于肠上皮细胞的GCN2表达，以及这些影响 都依赖于下游的激酶eIF2α。 目的2：确定过量的活性氧(ROS)的原因和后果 GCN2基因缺陷小鼠的生产。我们的初步数据显示，GCN2-/-小鼠的肠道功能增强 炎症和肠道树突状细胞和上皮细胞中ROS水平的升高。在这个目标中，我们建议确定 GCN2-/-小鼠体内ROS产生过多的原因和后果。 目的3：探讨GCN2抑制炎性小体激活的机制。最后， 我们的初步数据显示，在肠道DC和上皮细胞中炎性小体激活增加 GCN2-/-小鼠。在这个目标中，我们将确定这种炎性小体的激活是否对增强 肠道炎症和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洞察力 通路控制肠道炎症，并提供对抗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.