Key Points
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Distinct T cell lineages have unique metabolic needs. CD4+ and CD8+ effector T cells require specific metabolic programmes that differ from those that are required by memory or regulatory T cells.
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T cell activation, differentiation and function require the upregulation of appropriate metabolic programmes.
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The MYC, hypoxia-inducible factor 1α, mammalian target of rapamycin and AMP-activated protein kinase pathways regulate cellular metabolic function and direct the outcome of T cell differentiation.
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Targeting these metabolic pathways represents a novel means of regulating immune responses.
Abstract
Over the past decade, our understanding of T cell activation, differentiation and function has markedly expanded, providing a greater appreciation of the signals and pathways that regulate these processes. It has become clear that evolutionarily conserved pathways that regulate stress responses, metabolism, autophagy and survival have crucial and specific roles in regulating T cell responses. Recent studies suggest that the metabolic pathways involving MYC, hypoxia-inducible factor 1α (HIF1α), AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are activated upon antigen recognition and that they are required for directing the consequences of T cell receptor engagement. The purpose of this Review is to provide an integrated view of the role of these metabolic pathways and of canonical T cell signalling pathways in regulating the outcome of T cell responses.
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Acknowledgements
The authors thank F. Pan for critical review of this manuscript. The authors' work is supported by the US National Institutes of Health (grant R01AI077610-01A2). The authors apologize to those colleagues whose work has not been cited owing to space constraints.
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Glossary
- Glucose transporter type 1
-
(GLUT1). A unidirectional transporter that facilitates the transport of glucose across the plasma membrane.
- Lactate dehydrogenase A
-
(LDHA). An enzyme that catalyses the conversion of pyruvate to lactate.
- Hexokinase 2
-
An enzyme that initiates the first reaction of glycolysis by phosphorylating glucose to produce glucose-6-phosphate.
- Pyruvate dehydrogenase kinase 1
-
(PDK1). An enzyme that phosphorylates and inactivates pyruvate dehydrogenase, thereby inhibiting the catalysis of pyruvate to acetyl-CoA and preventing the initiation of the tricarboxylic acid cycle.
- Phosphofructokinase 1
-
A rate-limiting enzyme of glycolysis that requires ATP to convert fructose-6-phosphate into fructose-1,6-bisphosphate.
- Carnitine palmitoyltransferase 1A
-
(CPT1A). A rate-limiting mitochondrial enzyme that is necessary for fatty acid oxidation. CPT1A catalyses the transfer of the acyl group of long-chain fatty acids to acylcarnitine, which allows for its transport from the cytosol to the mitochondria.
- Autophagy
-
An evolutionarily conserved process in which acidic double-membrane-bound vacuoles sequester intracellular contents (such as damaged organelles and macromolecules) and target them for degradation through fusion with secondary lysosomes.
- α-ketoglutarate
-
A key intermediate of the tricarboxylic acid cycle that can be derived from glutaminolysis.
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Pollizzi, K., Powell, J. Integrating canonical and metabolic signalling programmes in the regulation of T cell responses. Nat Rev Immunol 14, 435–446 (2014). https://doi.org/10.1038/nri3701
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DOI: https://doi.org/10.1038/nri3701
