Key Points
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The kinase mTOR (mammalian target of rapamycin) is part of an evolutionarily conserved pathway that couples cell growth and metabolism to inputs from the environment in all eukaryotes. mTOR exists in two multiprotein complexes in metazoans, mTOR complex 1 (mTORC1) and mTORC2, which have distinct molecular compositions, cellular actions and physiological functions.
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T cells depend on mTOR signalling to sense and integrate immune signals from dendritic cells (including antigenic signals, co-stimulatory molecules and cytokines), environmental cues derived from growth factors and immunoregulatory factors, and nutrients.
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Under steady-state conditions, mTOR activity is tightly controlled by multiple inhibitory molecules — in particular the tumour suppressors PTEN (phosphatase and tensin homologue), TSC1 (tuberous sclerosis 1) and LKB1 (liver kinase B1) — to enforce the normal homeostasis of T cells. Loss of these control mechanisms disrupts the development and maintenance of T cells.
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Antigen recognition triggers robust mTOR activation, which drives the differentiation of naive CD4+ T cells into the T helper 1 (TH1), TH2 and TH17 cell effector lineages, while inhibiting the induction of regulatory T cells and T cell anergy. mTOR also promotes an effector fate over a memory fate for CD8+ T cells in infection and tumour immunity.
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mTOR serves as a signalling node to activate several downstream effector pathways, including immune receptor signalling, metabolic programmes and migratory activity. The coordination of these pathways by mTOR is important to achieve a productive immune response.
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Inhibition of mTOR induces immunosuppression in transplant rejections and autoimmune disorders, but also represents a promising strategy for vaccine development to boost immunity against pathogens and tumours. More potent and selective inhibitors of mTOR and mTOR-associated pathways are being developed for clinical and research purposes.
Abstract
The evolutionarily conserved kinase mTOR (mammalian target of rapamycin) couples cell growth and metabolism to environmental inputs in eukaryotes. T cells depend on mTOR signalling to integrate immune signals and metabolic cues for their proper maintenance and activation. Under steady-state conditions, mTOR is actively controlled by multiple inhibitory mechanisms, and this enforces normal T cell homeostasis. Antigen recognition by naive CD4+ and CD8+ T cells triggers mTOR activation, which in turn programmes the differentiation of these cells into functionally distinct lineages. This Review focuses on the signalling mechanisms of mTOR in T cell homeostatic and functional fates, and discusses the therapeutic implications of targeting mTOR in T cells.
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Acknowledgements
I acknowledge the large number of researchers who have contributed to this field whose work was not cited owing to space limitations. I thank R. Wang and Y. Wang for critical comments on the manuscript, and members of my laboratory for helpful discussions. The author's research is supported by the US National Institutes of Health (K01 AR053573 and R01 NS064599), the National Multiple Sclerosis Society (RG4180-A-1), the Lupus Research Institute, the Cancer Research Institute and the American Lebanese Syrian Associated Charities.
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Glossary
- Metabolism
-
Intracellular chemical reactions that convert nutrients and endogenous molecules into energy and biomass (proteins, nucleic acids and lipids). Naive T cells have a catabolic metabolism through which they use glucose, fatty acids and amino acids for ATP generation via the tricarboxylic acid cycle and oxidative phosphorylation. On antigen stimulation, the bioenergetic demands of a T cell increase dramatically and the cells transition into anabolic metabolism mediated by glycolysis and glutaminolysis.
- AMP-activated protein kinase
-
(AMPK). A group of serine/threonine kinases that are activated in response to energy depletion. AMPK is an important activator of fatty acid oxidation and a potent inhibitor of mTORC1.
- Regulatory T cells
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(TReg cells). A subset of CD4+ T cells that expresses FOXP3 and is crucial for the maintenance of immune tolerance. Although TReg cells mainly develop in the thymus as a separate lineage of CD4+ T cells, known as naturally occurring TReg cells, a second subset of TReg cells (known as induced TReg cells) arises de novo from conventional T cells in the periphery following antigen stimulation in the presence of TGFβ.
- Invariant natural killer T cells
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(iNKT cells). A subset of immune cells that shares properties with both T cells and natural killer cells.
- Central tolerance
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A process that eliminates self-reactive lymphocytes during their development. For T cells, this occurs mainly through clonal deletion in the thymus.
- Peripheral tolerance
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A process that downregulates the activation of self-reactive T cells in secondary lymphoid organs. Two of the most important mechanisms are suppression by regulatory T cells and the induction of T cell anergy.
- Catabolic metabolism
-
The breakdown of complex substances into simpler ones, which is often accompanied by ATP production. Examples include the oxidation of fatty acids and amino acids.
- Oxidative phosphorylation
-
A metabolic pathway that produces ATP from the oxidation of nutrients and the transfer of electrons in a two-step process in mitochondria. The first reaction involves the conversion of intermediate molecules (pyruvate and fatty acids) into acetyl-CoA, which enters the tricarboxylic acid cycle, yielding free electrons that are carried by NADH and FADH2. In the second reaction, electrons from NADH and FADH2 are transferred to the electron-transport chain, resulting in the movement of protons out of the mitochondrial matrix and the generation of an electrochemical potential for ATP synthesis.
- Fatty acid oxidation
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An important metabolic process used to derive energy through the mobilization and oxidation of fatty acids, mainly in the mitochondrial matrix. Fatty acid oxidation is positively and negatively regulated by AMPK and mTOR, respectively.
- T cell anergy
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A state of T cell unresponsiveness to antigen stimulation in which T cells fail to proliferate and produce interleukin-2.
- Autophagy
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A recycling process in which the cell degrades cytoplasmic organelles and proteins in lysosomes.
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Chi, H. Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol 12, 325–338 (2012). https://doi.org/10.1038/nri3198
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DOI: https://doi.org/10.1038/nri3198
