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Metabolism, migration and memory in cytotoxic T cells

Key Points

  • The serine/threonine kinase AKT does not have an obligatory role in controlling T cell metabolism.

  • Members of the AMP-activated protein kinase (AMPK) family have a role in T cell metabolism.

  • AKT controls T cell migration by regulating the expression of multiple adhesion and chemokine receptors that are crucial for homing to lymphoid tissues.

  • Distinct magnitudes of AKT activity are required for different AKT functions — T cell proliferation versus T cell migration.

  • The energy-sensing kinases mammalian target of rapamycin (mTOR) and AMPK may control T cell memory through a mechanism involving the control of T cell migration rather than T cell metabolism.

  • Differential levels of mTOR and AKT activity resulting from differences in T cell receptor and/or cytokine signalling strength could determine whether naive CD8+ T cells differentiate into effector cells or memory cells.

Abstract

The transcriptional and metabolic programmes that control CD8+ T cells are regulated by a diverse network of serine/threonine kinases. The view has been that the kinases AKT and mammalian target of rapamycin (mTOR) control T cell metabolism. Here, we challenge this paradigm and discuss an alternative role for these kinases in CD8+ T cells, namely to control cell migration. Another emerging concept is that AMP-activated protein kinase (AMPK) family members control T cell metabolism and determine the effector versus memory fate of CD8+ T cells. We speculate that one link between metabolism and immunological memory is provided by kinases that originally evolved to control T cell metabolism and have subsequently acquired the ability to control the expression of key transcription factors that regulate CD8+ T cell effector function and migratory capacity.

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Figure 1: Mechanism of AKT activation.
Figure 2: AKT-mediated control of adhesion and chemokine receptor expression.
Figure 3: Regulation of mTORC1 activity.
Figure 4: mTORC1 regulation of effector versus memory CD8+ T cell fate.
Figure 5: Model for how differential AKT and mTOR signalling controls effector versus memory CD8+ T cell formation.

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Glossary

14-3-3 scaffold proteins

A family of conserved proteins that are present in all eukaryotic organisms. These proteins are involved in diverse cellular processes, such as apoptosis and stress, as well as in intracellular signalling and cell-cycle regulation. They function as adaptors in protein interactions and can regulate protein localization and enzymatic activity. Approximately 100 binding partners have been reported for the 14-3-3 proteins.

Aerobic glycolysis

Glycolysis is an anaerobic metabolic pathway that converts glucose to pyruvate, which can then be either further metabolized in the presence of oxygen to generate ATP through oxidative phosphorylation, or converted to lactate. The term 'aerobic glycolysis' describes the conversion of glucose to lactate even though oxygen is present and thus not a limiting factor. For example, most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytoplasm, whereas most normal cells use a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria (termed the Warburg effect).

β-selection

A process involving a cell autonomous signalling cascade that leads to the proliferation and survival of thymocytes that have undergone successful recombination at the locus that encodes the β-chain of the T cell receptor (TCR) to express a functional pre-TCR on their cell surface.

Granzymes

Secreted serine proteases that enter target cells through perforin pores, where they then cleave and activate intracellular caspases to initiate target-cell apoptosis.

L-system amino acid transporter 1

A heterodimeric membrane transport protein that preferentially transports neutral branched amino acids (such as valine, leucine and isoleucine) and aromatic amino acids (such as tryptophan and tyrosine).

Mammalian target of rapamycin

(mTOR). A conserved serine/threonine protein kinase that can regulate cell growth and metabolism in response to environmental cues. mTOR receives stimulatory signals from RAS and phosphoinositide 3-kinase (PI3K) downstream of growth factors and nutrients, such as amino acids, glucose and oxygen.

Oxidative phosphorylation

A metabolic process that encompasses two sets of reactions that occur in the mitochondria. 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.

Perforin

A component of cytolytic granules that participates in the permeabilization of plasma membranes, allowing granzymes and other cytotoxic components to enter target cells.

Rapamycin

An immunosuppressive drug that blocks mTOR.

Rate-limiting glycolytic enzymes

The enzymes hexokinase, phosphofructokinase and pyruvate kinase, which catalyse the three enzymatic steps in the glycolytic pathway that are essentially irreversible. Allosteric, transcriptional and post-translational regulation of these enzymes is crucial for the regulation of glycolysis. Phosphofructokinase catalyses the main rate-limiting step of glycolysis and is the most important control point.

Transferrin receptor

(Also known as CD71). A receptor that regulates the cellular import of iron by binding the iron-carrier protein transferrin.

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Finlay, D., Cantrell, D. Metabolism, migration and memory in cytotoxic T cells. Nat Rev Immunol 11, 109–117 (2011). https://doi.org/10.1038/nri2888

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