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Regulation of innate immune cell function by mTOR

Key Points

  • Mammalian target of rapamycin (mTOR) is an evolutionarily conserved serine/threonine kinase that is present in two complexes: mTORC1 and mTORC2. mTORC1 is the main energy and nutrient sensor of the cell: it senses the presence of amino acids, glucose, lipids and ATP to enable efficient activation of the network in response to growth factors, Toll-like receptor (TLR) ligands and cytokines.

  • Activation of the mTOR pathway usually promotes an anabolic response that induces the synthesis of nucleic acids, proteins and lipids. In addition, it stimulates glycolysis and mitochondrial respiration. Emerging data suggest that this metabolic reconfiguration is required for specific effector functions in myeloid cells.

  • Translational control of gene expression in myeloid immune cells has emerged as one way in which mTORC1 controls cellular processes such as migration, expression of type I interferon and pro-inflammatory or anti-inflammatory cytokines, and metabolic reprogramming.

  • Counterintuitively, inhibition of mTORC1 during TLR triggering generally promotes interleukin-12 (IL-12) production and inhibits expression of IL-10 and type I interferon by dendritic cells (DCs); it also augments their T cell-stimulatory capacity. Inhibition of mTORC2 enhances a pro-inflammatory response and IL-12 production in DCs.

  • Inhibition of mTORC1 in macrophages promotes autophagy, which is important for intracellular pathogen killing and clearance of ingested complex lipids such as low-density lipoprotein (LDL) cholesterol.

  • mTORC2 is especially important for cell polarity and chemotaxis in neutrophils and mast cells. mTORC2 controls the leading edge as well as tail retraction during chemotactic migration.

  • Activation of mTORC1 in NK cells by IL-15 triggers a glycolytic response, which is important for their proliferation and acquisition of cytotoxicity.

Abstract

The innate immune system is central for the maintenance of tissue homeostasis and quickly responds to local or systemic perturbations by pathogenic or sterile insults. This rapid response must be metabolically supported to allow cell migration and proliferation and to enable efficient production of cytokines and lipid mediators. This Review focuses on the role of mammalian target of rapamycin (mTOR) in controlling and shaping the effector responses of innate immune cells. mTOR reconfigures cellular metabolism and regulates translation, cytokine responses, antigen presentation, macrophage polarization and cell migration. The mTOR network emerges as an integrative rheostat that couples cellular activation to the environmental and intracellular nutritional status to dictate and optimize the inflammatory response. A detailed understanding of how mTOR metabolically coordinates effector responses by myeloid cells will provide important insights into immunity in health and disease.

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Figure 1: The mTOR pathway in innate immune cells.
Figure 2: Metabolic control by mTOR in innate immunity.
Figure 3: mTOR in dendritic cells and its effects on T cell activation.
Figure 4: mTOR in neutrophils, mast cells and natural killer cells.

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Acknowledgements

This work was supported by grants from the Austrian Science Fund (FWF; grant FWF-P27701-B20), the Else Kröner-Fresenius-Stiftung (P2013_A149) and the Herzfelder'sche Familienstiftung. The authors apologize to those colleagues whose work has not been cited owing to space constraints.

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Glossary

mTOR complex 1

(mTORC1). A complex consisting of: mammalian target of rapamycin (mTOR), which is a serine/threonine kinase; regulatory-associated protein of mTOR (RAPTOR); proline-rich AKT1 substrate of 40 kDa (PRAS40), which is an mTORC1 inhibitor; mLST8 (also known as GβL), which is of unknown function; and DEP domain-containing mTOR-interacting protein (DEPTOR), which is an mTOR inhibitor.

mTORC2

A complex composed of: mammalian target of rapamycin (mTOR), mLST8 and the adaptor proteins rapamycin-insensitive companion of mTOR (RICTOR) and stress-activated MAP kinase-interacting protein 1 (SIN1).

Tuberous sclerosis 1

(TSC1). TSC1 forms a heterodimeric complex with TSC2. The TSC1–TSC2 complex actively inhibits mammalian target of rapamycin complex 1 (mTORC1) in unstimulated cells. Stimulation promotes AKT-dependent phosphorylation and inactivation of the complex. TSC1–TSC2 seems to be a positive regulator of mTORC2.

Pyruvate

The end product of glycolysis, which can be further metabolized to lactate in a process known as aerobic glycolysis (also known as the Warburg effect). Pyruvate can also be oxidized in the mitochondria through the tricarboxylic acid (TCA) cycle followed by oxidative phosphorylation to generate ATP.

Langerhans cells

A specialized subset of dendritic cells that seed the epidermal layer of the skin.

M1 and M2 macrophage subsets

Macrophages display considerable plasticity and can change their function in response to local environmental stimuli. M1 (or classically activated) macrophages mediate defence against various pathogens and tumours and contribute to chronic inflammatory diseases and autoimmunity. M2 (or alternatively activated) macrophages are required for defence against parasitic infections, to promote the resolution of inflammation, and to initiate tissue repair, and they are also implicated in promoting tumour growth.

STAT6

(Signal transducer and activator of transcription 6). A transcription factor that is important for M2 macrophage polarization after stimulation with interleukin-4 (IL-4) or IL-13. STAT6 regulates many M2 macrophage-associated genes, such as those encoding arginase 1, CD206, resistin-like-α and chitinase-like protein 3 (also known as YM1).

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Weichhart, T., Hengstschläger, M. & Linke, M. Regulation of innate immune cell function by mTOR. Nat Rev Immunol 15, 599–614 (2015). https://doi.org/10.1038/nri3901

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