Mechanistic relationships between IDO, GCN2, and mTOR signals in immunity to apoptotic cells

 描述（由申请人提供）： 脾是产生对凋亡细胞的系统耐受所必需的。我们最近已经表明，一组专门的巨噬细胞居住在边缘区的红髓驱动免疫耐受凋亡的材料，在他们的情况下，凋亡细胞诱导炎症和自身免疫反应。虽然尚不清楚这在机制水平上是如何发生的，但我们已经发现凋亡细胞引发了一种聚糖分解代谢酶吲哚胺2，3双加氧酶（IDO）的表达，这对于各种炎症环境中的免疫抑制至关重要。此外，我们发现IDO的阻断极大地改变了巨噬细胞和树突状细胞对凋亡细胞的反应方式，增加了狼疮易感动物的炎症免疫和自身免疫性疾病活性。因此，数据表明了一种新的机制，其中巨噬细胞中的IDO活性控制对凋亡细胞的先天性和适应性免疫。我们提出的项目将研究凋亡细胞驱动的IDO活性如何影响边缘区巨噬细胞中的mTOR信号，IDO驱动的色氨酸代谢如何影响凋亡细胞介导的耐受性，以及IDO可能影响Treg激活的机制;最后在系统性红斑狼疮的实验模型中测试这些机制。因此，该项目的发现可能对免疫力低下和免疫力过高的疾病具有巨大的影响，其中致耐受性变阻器的调节将提供显著的临床益处。

 DESCRIPTION (provided by applicant): The spleen is required for the generation of systemic tolerance to apoptotic cells. We have recently shown a specialized set of macrophages residing in the marginal zone region of the red pulp drive immunologic tolerance to apoptotic material and in their absence apoptotic cells induce inflammation and autoimmune reactivity. While it is not known how this occurs on a mechanistic level, we have found apoptotic cells provoke expression of a tryptophan-catabolizing enzyme, indoleamine 2, 3 dioxygenase (IDO), which is critical for immune suppression in a variety of inflammatory settings. Further we discovered blockade of IDO greatly altered the way macrophages and dendritic cells respond to apoptotic cells with increased inflammatory immunity and autoimmune disease activity in lupus-prone animals. Thus the data suggest a novel mechanism whereby IDO activity in macrophages controls both innate and adaptive immunity to apoptotic cells. Our proposed project will examine how apoptotic cells driven IDO activity impacts mTOR signals in marginal zone macrophages, how IDO-driven tryptophan metabolism impacts apoptotic cell-mediated tolerance, and mechanisms by which IDO may influence Treg activation; finally testing these mechanisms in an experimental model of systemic lupus erythematosus. Thus, the findings of this project could have enormous implications in diseases of hypo and hyper-immunity where modulation of the tolerogenic rheostat would provide significant clinical benefit.