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.

Public Health Relevance

Dendritic cells (DCs) play key roles in orchestrating immunity to pathogens. Multiple subsets of functionally specialized DCs exist, but DC function can also be modulated by microbial and tissue-derived stimuli. We have recently demonstrated a major role for the metabolic sensors mTOR and GCN2 in regulating DC development and function, and the underlying mechanisms of this ?metabolic imprinting? will be explored.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Davidson, Wendy F
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Stanford University
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