Metabolic imprinting of dendritic cell fate and function in tissues

摘要 树突状细胞（Dendritic cells，DC）在感知病原体和调节免疫应答中起着重要作用。 功能不同的DC亚群可以刺激不同类型的免疫应答，但DC 也显示出响应微生物刺激或来自组织的信号的功能可塑性 微环境然而，现在很清楚，DCs不仅能感受到微生物刺激， 各种应激信号（例如氨基酸饥饿），通过古老的应激感测机制， 导致它们功能的代谢重编程。特别是我们最近的工作 揭示了两种主要氨基酸传感器GCN 2和mTOR的基本作用， 编程DC以调节适应性免疫和炎症。我们已经证明，GCN 2 在对DC进行编程以响应病毒疫苗接种以及在控制肠道免疫中起作用。 通过促进肠道APC中的自噬和抑制炎性体活化来调节炎症 和上皮细胞。此外，我们最近的数据表明，GCN 2调节过敏性 肺部炎症。除了GCN 2的这些影响外，我们最近还表明， mTOR调节肺中DC和肺泡巨噬细胞（AM）的发育命运， 重新编程他们的代谢状态以调节过敏性炎症的结果。在 以下的目的，我们将确定这种代谢印记的机制。 目的1：确定mTOR控制体内稳态的机制， 肺DC和AM在稳态和变应性炎症期间的功能。我们 最近的研究表明，在小鼠中，mTOR在CD 11 c+细胞中被遗传消融， （mTORAPC小鼠）：（i）肺中的CD 103 + DC和AM的数量大大减少，在mTORAPC小鼠中， 稳态(ii)虽然肺CD 11 c + CD 11b + DC在数值上未受影响，但它们在肺组织中的表达与肺组织中的表达无关。 其转录特性偏向于巨噬细胞/单核细胞谱。(iii)肺 过敏性Th 2炎症倾向于Th 17/嗜中性表型。本 目的，我们将研究这些影响的机制，并研究潜在的 4 E-BP 3依赖的翻译控制、脂质代谢和表观遗传重编程在 介导mTOR信号传导的作用。 目的2：确定GCN 2调节Th 2应答的机制， 过敏性炎症我们的初步数据表明，GCN 2基因敲除小鼠显示， 显著减少肺部过敏性炎症。在这个目标中，我们将确定 这种影响的机制。这些目标的成功实现将产生丰富的 关于DC命运和功能的代谢印记的机制见解。

ABSTRACT Dendritic cells (DCs) play a central role in sensing pathogens and tuning immune responses. Functionally distinct subsets of DCs can stimulate different types of immune responses, but DCs also display functional plasticity in response to microbial stimuli or signals from the tissue microenvironment. However, it is now clear that DCs sense not just microbial stimuli, but also various stress signals (e.g. amino acid starvation), through ancient stress sensing mechanisms, leading to a metabolic reprogramming of their function. In particular our recent work has revealed fundamental roles for two major amino acid sensors GCN2 and mTOR, in programming DCs to modulate adaptive immunity and inflammation. We have shown that GCN2 plays a role in programming DCs to respond to viral vaccination, and in controlling intestinal inflammation by promoting autophagy and suppressing inflammasome activation in gut APCs and epithelial cells. Furthermore, our recent data demonstrates that GCN2 regulates allergic inflammation in the lung. In addition to these effects of GCN2, we have recently shown that mTOR regulates developmental fate of DCs and alveolar macrophages (AMs) in the lung, and reprograms their metabolic state to modulate the outcome of allergic inflammation. In the following aims, we will determine the mechanisms of this metabolic imprinting. Aim 1: To determine the mechanisms by which mTOR controls the homeostasis and function of lung DCs and AMs in the steady state and during allergic inflammation. Our recent work demonstrates that in mice in which mTOR is genetically ablated in CD11c+ cells (mTORAPC mice): (i) CD103+ DCs and AMs in the lung are greatly reduced in number, in the steady state. (ii) Although the lung CD11c+CD11b+ DCs were numerically unaffected, they were skewed in their transcriptional identity towards the macrophage/monocytic profile. (iii) Lung allergic Th2 inflammation was skewed toward the Th17/neutrophilic phenotype. In the present aim, we will investigate the mechanisms underlying these effects, and investigate the potential role of 4E-BP3 dependent translational control, lipid metabolism and epigenetic reprograming in mediating the effects of mTOR signaling. Aim 2: To determine the mechanisms by which GCN2 regulates Th2 responses and allergic inflammation. Our preliminary data demonstrate that GCN2 knockout mice display markedly reduced allergic inflammation in the lung. In this aim we will determine the molecular mechanisms underlying this effect. The successful completion of these aims will yield rich mechanistic insights about metabolic imprinting of DC fate and function.