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

• Type of Material: Article
• Authors: Charles Sinclair, Emory University; Gayathri Bommakanti, Emory University; Luiz Gardinassi, Emory University; Jens Loebbermann, Emory University; Matthew Joseph Johnson, Emory University; Paul Hakimpour, Emory University; Thomas Hagan, Emory University; Lydia Benitez, Emory University; Andrei Todor, Emory University; Deepa Machiah, Emory University; Timothy Oriss, University of Pittsburgh; Anuradha Ray, University of Pittsburgh; Steven Bosinger, Emory University; Rajesh Ravindran, Emory University; Shuzhao Li, Emory University; Bali Pulendran, Emory University
• Language: English
• Date: 2017-09-08
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1126/science.aaj2155
• Title of Journal or Parent Work: Science
• ISSN: 0036-8075
• Volume: 357
• Issue: 6355
• Start Page: 1014
• End Page: +
• Grant/Funding Information: This work was supported by funding from Action Cycling Atlanta and from the People Programme (Marie Curie Actions) of the European Union’s Seventh Framework Programme (FP7/2007–2013) (C.S.) and from the U.S. National Institutes of Health (grants R37 DK057665, R37 AI048638, U19 AI090023, and U19 AI057266) (B.P.).
• Keywords: Science & Technology - Other Topics; MAMMALIAN TARGET; Science & Technology; DIFFERENTIATION; HOMEOSTASIS; CONVENTIONAL DENDRITIC CELLS; FLT3 LIGAND; MECHANISTIC TARGET; SENSOR GCN2; PULMONARY ALVEOLAR PROTEINOSIS; Multidisciplinary Sciences; RAPAMYCIN; INFLUENZA-VIRUS
• Research Categories: Health Sciences, Pathology; Health Sciences, Immunology

Abstract

Antigen-presenting cells (APCs) occupy diverse anatomical tissues, but their tissuerestricted 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.