mTORC2 Deficiency Alters the Metabolic Profile of Conventional Dendritic Cells

Front Immunol. 2019 Jul 2;10:1451. doi: 10.3389/fimmu.2019.01451. eCollection 2019.


In myeloid dendritic cells (DC), deletion of the mechanistic target of rapamycin complex 2 (TORC2) results in an augmented pro-inflammatory phenotype and T cell stimulatory activity; however, the underlying mechanism has not been resolved. Here, we demonstrate that mouse bone marrow-derived TORC2-deficient myeloid DC (TORC2-/- DC) utilize an altered metabolic program, characterized by enhanced baseline glycolytic function compared to wild-type WT control (Ctrl) DC, increased dependence on glycolytic ATP production, elevated lipid content and higher viability following stimulation with LPS. In addition, TORC2-/- DC display an increased spare respiratory capacity (SRC) compared to WT Ctrl DC; this metabolic phenotype corresponds with increased mitochondrial mass and mean mitochondrial DNA copy number, and failure of TORC2-/- DC mitochondria to depolarize following LPS stimulation. Our data suggest that the enhanced metabolic activity of TORC2-/- DC may be due to compensatory TORC1 pathway activity, namely increased expression of multiple genes upstream of Akt/TORC1 activity, including the integrin alpha IIb, protein tyrosine kinase 2/focal adhesion kinase, IL-7R and Janus kinase 1(JAK1), and the activation of downstream targets of TORC1, including p70S6K, eukaryotic translation initiation factor 4E binding protein 1 (4EBP1) and CD36 (fatty acid translocase). These enhanced TORC1 pathway activities may culminate in increased expression of the nuclear receptor peroxisome proliferator-activated receptor γ (Pparγ) that regulates fatty acid storage, and the transcription factor sterol regulatory element-binding transcription factor 1 (Srebf1). Taken together, our data suggest that TORC2 may function to restrain TORC1-driven metabolic activity and mitochondrial regulation in myeloid DC.

Keywords: dendritic cells; mammalian target of rapamycin complex 2; metabolism; mitochondrial regulation; mouse; rapamycin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Respiration / drug effects
  • Cell Respiration / genetics
  • DNA, Mitochondrial
  • Dendritic Cells / metabolism*
  • Glycolysis / drug effects
  • Glycolysis / genetics
  • Golgi Apparatus / metabolism
  • Lipid Droplets / metabolism
  • Lipopolysaccharides / pharmacology
  • Mechanistic Target of Rapamycin Complex 1 / antagonists & inhibitors
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mechanistic Target of Rapamycin Complex 2 / deficiency*
  • Mechanistic Target of Rapamycin Complex 2 / genetics
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria / drug effects
  • Mitochondria / genetics
  • NF-kappa B / metabolism
  • Phenotype*
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Signal Transduction / genetics*
  • Sirolimus / pharmacology
  • Transcriptome


  • DNA, Mitochondrial
  • Lipopolysaccharides
  • NF-kappa B
  • Mechanistic Target of Rapamycin Complex 1
  • Mechanistic Target of Rapamycin Complex 2
  • Ribosomal Protein S6 Kinases, 70-kDa
  • Sirolimus