Research Article

mTOR regulates metabolic adaptation of APCs in the lung and controls the outcome of allergic inflammation

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Science  08 Sep 2017:
Vol. 357, Issue 6355, pp. 1014-1021
DOI: 10.1126/science.aaj2155

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Metabolic programming of tissue APCs

Antigen-presenting cells (APCs) are scattered throughout the body in lymphoid organs and at the portals of pathogen entry, where they act as sentinels of the immune system. Sinclair et al. demonstrate that APCs at different sites have distinctive metabolic signatures and that the development and function of these cells are determined not only by their transcriptional program, but also by their metabolic state (see the Perspective by Wiesner and Klein). The authors identified a central role for mTOR in mediating the metabolic adaptation of such tissue-resident APCs by influencing the immunological character of allergic inflammation. Thus, tissues endow resident APCs with distinctive metabolic characteristics that control APC development and function.

Science, this issue p. 1014; see also p. 973

Abstract

Antigen-presenting cells (APCs) occupy diverse anatomical tissues, but their tissue-restricted homeostasis remains poorly understood. Here, working with mouse models of inflammation, we found that mechanistic target of rapamycin (mTOR)–dependent metabolic adaptation was required at discrete locations. mTOR was dispensable for dendritic cell (DC) homeostasis in secondary lymphoid tissues but necessary to regulate cellular metabolism and accumulation of CD103+ DCs and alveolar macrophages in lung. Moreover, while numbers of mTOR-deficient lung CD11b+ DCs were not changed, they were metabolically reprogrammed to skew allergic inflammation from eosinophilic T helper cell 2 (TH2) to neutrophilic TH17 polarity. The mechanism for this change was independent of translational control but dependent on inflammatory DCs, which produced interleukin-23 and increased fatty acid oxidation. mTOR therefore mediates metabolic adaptation of APCs in distinct tissues, influencing the immunological character of allergic inflammation.

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