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  • Review Article
  • Published:

Fuel feeds function: energy metabolism and the T-cell response

Nature Reviews Immunology volume 5, pages 844–852 (2005)Cite this article

Key Points

  • For all cells, a constant supply of intracellular metabolites is required to sustain the most vital tasks of the cell. Nutrients such as glucose, amino acids and fatty acids can be degraded into simpler intermediates to provide metabolic energy in the form of ATP. The same intermediates can be used to build macromolecules such as proteins and lipids at the expense of ATP.

  • In the peripheral circulation, glucose, amino acids and fatty acids are maintained at relatively constant concentrations. In the absence of instructional extracellular signals that are delivered through the ligation of cytokine, antigen or co-stimulatory receptors, lymphocytes lack the ability to take up sufficient nutrients to maintain even their basic bioenergetic needs.

  • T cells have evolved the capacity to switch between states of relative quiescence and rapid proliferative expansion. These two fates are regulated, in part, by signals that are delivered through cytokine and antigen receptors, the outcome of which is closely coupled to the differentiation state of the responding cell.

  • Rather than a default response to a lack of mitogenic signals, quiescence in T cells is an actively maintained state with unique metabolic demands. Resting T cells derive most of their ATP from the oxidative phosphorylation of intracellular metabolites, and they use this energy to suppress actively the expression of cell-cycle proteins through regulated protein degradation.

  • Although activated lymphocytes are preparing to commit to the energy-demanding process of proliferation, they hyperinduce glycolysis and preferentially excrete pyruvate as lactate, even when oxygen is not present in limiting concentrations. This indicates that glucose uptake and utilization is a required part of the metabolic response of T cells to mitogenic signals.

  • Rapamycin, which inhibits TOR (target of rapamycin), is a powerful immunosuppressant that functions by targeting cellular metabolism. In addition to enzymes of the phosphatidylinositol-3-kinase pathway, the kinases PIM1 and PIM2 are important contributors to the rapamycin sensitivity of lymphocytes in vivo and in vitro.

Abstract

Ligation of antigen receptors at the surface of lymphocytes initiates a transcriptional and translational response that is required for cellular proliferation and effector function. By contrast, co-stimulatory-molecule ligation contributes to the immune response by allowing the uptake and utilization of extracellular nutrients to provide energy for cellular proliferation and effector functions. Growth factors also potentiate the ability of lymphocytes to metabolically switch between resting and proliferative states. Lymphocytes that do not receive these signals fail to increase their metabolism to meet the higher bioenergetic demands of cell growth and are either deleted or rendered unresponsive to mitogenic signals. In this Review, we describe how T cells actively acquire metabolic substrates from their environment to meet these energy demands and respond appropriately to pathogens.

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Figure 1: Growth factors regulate nutrient uptake.
Figure 2: AKT and TOR, and PIM1 and PIM2, regulate key metabolic pathways.

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Acknowledgements

We thank J. Gruber and T. Lindsten for their critical assessment of the manuscript. C.J.F. is supported by a fellowship from The Leukemia & Lymphoma Society (United States). P.S.H. is a recipient of a Pre-doctoral Training Grant from the Cancer Research Institute (United States). Funding to support the laboratory of C.B.T. is provided, in part, by the National Institutes of Health (United States).

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Authors and Affiliations

  1. Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Casey J. Fox, Peter S. Hammerman & Craig B. Thompson

  2. Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Casey J. Fox, Peter S. Hammerman & Craig B. Thompson

Authors
  1. Casey J. Fox
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  2. Peter S. Hammerman
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  3. Craig B. Thompson
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Correspondence to Craig B. Thompson.

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DATABASES

Entrez Gene

AKT

AMPK

4EBP1

EIF4E

GLUT1

PIM1

PIM2

RHEB

TOR

Glossary

GLYCOLYSIS

A metabolic process that occurs in the cytosol and breaks down one molecule of glucose into two molecules of pyruvate, resulting in the production of ATP. Pyruvate is converted to lactate, which regenerates the NAD that is required as an electron acceptor in this catabolic process. Alternatively, pyruvate can be oxidized in the tricarboxylic-acid cycle, and NAD can be regenerated in one of two mitochondrial shuttles that end with electron donation to the electron-transport chain.

OXIDATIVE PHOSPHORYLATION

A metabolic process that encompasses two sets of reactions. The first reaction involves the conversion of intermediate molecules (pyruvate and fatty acids) to acetyl coenzyme A (acetyl-CoA) and the degradation of acetyl-CoA to carbon dioxide in the tricarboxylic-acid cycle, yielding free electrons that are carried by NADH and FADH2. The second reaction involves the transfer of electrons from NADH and FADH2 to the electron-transport chain, resulting in the movement of protons out of the mitochondrial matrix. The resulting electrochemical potential is used by the F1F0 ATP synthase to synthesize ATP.

CATABOLIC METABOLISM

The breakdown of complex substances into simpler ones. This often allows cells to capture the released reduction equivalents and channel them into ATP production. Examples include the oxidation of fatty acids and amino acids.

ANABOLIC METABOLISM

The synthesis of complex macromolecules from simpler intermediates at the expense of ATP. Examples include the synthesis of nucleotides from ribose-5-phosphate, lipids from acetyl coenzyme A, and proteins from amino acids.

AUTOPHAGY

An evolutionarily conserved process in which acidic double-membrane vacuoles sequester intracellular contents (such as damaged organelles and macromolecules) and target them for degradation, through fusion to secondary lysosomes.

AEROBIC GLYCOLYSIS

A metabolic process that is preferentially induced in proliferating lymphocytes and is also characteristic of neoplastic and transformed cells. In contrast to anaerobic conditions (such as in skeletal muscle and inflamed tissues), in which glycolysis is the main source of ATP, lymphocytes in the peripheral blood are not exposed to low oxygen concentrations; however, they continue to excrete excess pyruvate as lactate rather than fully oxidizing it in the tricarboxylic-acid cycle.

NECROSIS

Forms of cell death that result from a decline in cellular ATP or ADP levels below the concentration that is required to maintain cellular organization and integrity.

β-OXIDATION

The oxidative breakdown of fatty acids into acetyl coenzyme A (acetyl-CoA) by stepwise oxidation at the β-carbon atom. Each round of oxidation yields one NADH molecule and one FADH2 molecule, and the acetyl-CoA that is also produced enters the tricarboxylic-acid cycle.

CAP-DEPENDENT TRANSLATION

A mechanism for initiation of translation. It involves the binding of the EIF4F complex (which is composed of the mRNA helicase EIF4A (eukaryotic translation-initiation factor 4A), EIF4E, the scaffolding protein EIF4G and poly(A)-binding protein) to mRNA transcripts with a 5′ 7-methyl guanylate cap, resulting in recruitment of the 43S ribosome. The ribosome then scans the mRNA until it reaches the first AUG codon, and it initiates translation following the GTP-dependent release of EIF2B.

E3 UBIQUITIN LIGASE

A molecule that has a key role in protein turnover. It recognizes substrate proteins with a high degree of specificity and targets them to the ubiquitin-dependent proteasomal machinery. E3 ubiquitin ligases — including CBL (Casitas B-lineage lymphoma), ITCH and NEDD4 (neural precursor-cell expressed, developmentally downregulated 4) — are crucial regulators of the T-cell response to pro-survival and mitogenic signals.

CAP-INDEPENDENT TRANSLATION

The ability of certain mRNA transcripts to directly recruit the 43S ribosome without previous formation of a 5′ 7methyl guanylate cap. One way that this occurs is by internal ribosomal-entry sites (IRESs) that can directly interact with the 43S ribosome. IRES-dependent translation is one way that viruses can co-opt the cellular translation machinery to drive viral replication.

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Fox, C., Hammerman, P. & Thompson, C. Fuel feeds function: energy metabolism and the T-cell response. Nat Rev Immunol 5, 844–852 (2005). https://doi.org/10.1038/nri1710

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