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全身耐受所必需的。我们最近发现了位于红髓边缘区域的一组特殊的巨噬细胞驱动对凋亡物质的免疫耐受，在它们不存在的情况下，凋亡细胞诱导炎症和自身免疫反应。虽然目前还不知道这是如何在机制水平上发生的，但我们已经发现，凋亡细胞刺激色氨酸分解代谢酶吲哚胺2，3双加氧酶(IDO)的表达，IDO在各种炎症环境中对免疫抑制至关重要。此外，我们发现阻断IDO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，从而增强了狼疮易感动物的炎症免疫和自身免疫性疾病活动。因此，这些数据提示了一种新的机制，即巨噬细胞中的IDO活性控制对凋亡细胞的先天和获得性免疫。我们建议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，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，该项目的发现可能会对免疫功能低下和免疫功能亢进的疾病产生巨大的影响，在这些疾病中，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.