Key Points
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Naive, effector and memory T cells have distinct metabolic profiles that are crucial for their maintenance and function.
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A complex network of immune cell-specific transcription factors, cytokines and canonical regulators of cellular metabolism regulate the diversity of effector and memory T cells.
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The T cell receptor-dependent transcription factors interferon-regulatory factor 4 (IRF4) and MYC coordinately induce gene networks that are required for metabolic reprogramming and for sustaining aerobic glycolysis during periods of rapid clonal expansion.
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Clonal competition and the selection of high-affinity T cell clones during a primary immune response are driven by metabolic fitness.
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Common cytokine receptor γ-chain cytokines modulate metabolic profiles during effector and memory T cell differentiation and maintenance.
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Immune cell-specific transcription factors sense and integrate metabolic signals with immunological cues to appropriately regulate adaptive immune responses.
Abstract
During an immune response, cytokines and transcription factors regulate the differentiation and function of effector and memory T cells. At the same time, T cell metabolism undergoes dynamic and differentiation-stage-specific changes that are required for initial T cell activation, rapid proliferation and the acquisition of effector functions. Similarly, during the resolution of an immune response, metabolic regulation is crucial for restraining inflammatory responses and promoting peripheral tolerance, and it is required for the long-term maintenance of memory T cells. T cell receptor (TCR)-induced transcription factors, in particular MYC and interferon-regulatory factor 4 (IRF4), cooperate with canonical nutrient-sensing pathways to integrate antigen-specific and metabolic signals to appropriately modulate adaptive immune responses. In this Review, we focus on the emerging evidence that T cell differentiation and metabolism are closely linked and synchronized by immune cell-specific cytokines and transcription factors that are induced by TCR signalling.
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Acknowledgements
The authors thank the members of the Kallies laboratory for their various inputs. This work was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (A.K.), by fellowships from the Sylvia and Charles Viertel Foundation (A.K.) and the Victoria Cancer Council (K.M.), and by the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC Independent Research Institute Infrastructure Support scheme.
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Glossary
- Catabolic state
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A state of metabolism characterized by 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.
- Anabolic state
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A state of metabolism characterized by chemical reactions that build complex molecules from simpler units, consuming energy in the process.
- Oxidative phosphorylation
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A two-step metabolic pathway that produces ATP from the oxidation of nutrients and the transfer of electrons. First, pyruvate and fatty acids are converted into acetyl-CoA, which enters the tricarboxylic acid cycle, yielding free electrons carried by NADH and FADH2. Second, the electrons enter the electron transport chain, resulting in the movement of protons out of the mitochondrial matrix and the synthesis of ATP.
- Fatty acid oxidation
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(FAO). An important metabolic process used to derive energy through the mobilization and oxidation of fatty acids, mainly in the mitochondrial matrix. FAO is positively and negatively regulated by AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), respectively.
- Glycolysis
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Oxygen-independent metabolism of glucose and other sugars into pyruvate to produce energy in the form of ATP and intermediate substrates for other metabolic pathways. When combined with oxygen-dependent enzyme reactions, a more complete breakdown occurs, producing more energy.
- Glutaminolysis
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A series of biochemical reactions in which the amino acid glutamine is degraded to glutamate and then to α-ketoglutarate for further metabolism in the tricarboxylic acid cycle.
- mTOR complex 1
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(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.
- Tricarboxylic acid cycle
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Also known as Krebs cycle. Acetyl-CoA derived from glucose or fat breakdown is further metabolized to generate reduced energy equivalents that are used by mitochondrial oxidative phosphorylation to generate ATP.
- Oxysterols
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Natural molecules derived from cholesterol oxidation.
- T cell exhaustion
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A state in which effector T cells have an impaired ability to carry out their functions, such as cytotoxicity and cytokine secretion, owing to chronic stimulation by antigens. It is characterized by increased surface expression of inhibitory receptors such as programmed cell death protein 1.
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Man, K., Kallies, A. Synchronizing transcriptional control of T cell metabolism and function. Nat Rev Immunol 15, 574–584 (2015). https://doi.org/10.1038/nri3874
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DOI: https://doi.org/10.1038/nri3874
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