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Author Notes:

Corresponding author. bpulend@stanford.edu; bpulend@emory.edu

We thank V. Bliss and P. Sharma for histological support, G. Tharp and N. Patel for genomics analysis, V. Tran for metabolomics, B. Cervasi and K. Gill for FACS sorting, and H. Hartweger and E. Schweighoffer (Francis Crick Institute) for advice on B cell FACS staining.

Finally, we thank Pulendran laboratory members for discussion and M. Sinclair for proofreading the manuscript.

We are not aware of any conflicts of interest.

Subjects:

Research Funding:

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
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • PULMONARY ALVEOLAR PROTEINOSIS
  • CONVENTIONAL DENDRITIC CELLS
  • MECHANISTIC TARGET
  • MAMMALIAN TARGET
  • INFLUENZA-VIRUS
  • SENSOR GCN2
  • FLT3 LIGAND
  • RAPAMYCIN
  • DIFFERENTIATION
  • HOMEOSTASIS

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

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Journal Title:

Science

Volume:

Volume 357, Number 6355

Publisher:

, Pages 1014-+

Type of Work:

Article | Post-print: After Peer Review

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.

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© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

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