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CD8+ T cell metabolism in infection and cancer

Abstract

Cytotoxic CD8+ T cells play a key role in the elimination of intracellular infections and malignant cells and can provide long-term protective immunity. In the response to infection, CD8+ T cell metabolism is coupled to transcriptional, translational and epigenetic changes that are driven by extracellular metabolites and immunological signals. These programmes facilitate the adaptation of CD8+ T cells to the diverse and dynamic metabolic environments encountered in the circulation and in the tissues. In the setting of disease, both cell-intrinsic and cell-extrinsic metabolic cues contribute to CD8+ T cell dysfunction. In addition, changes in whole-body metabolism, whether through voluntary or disease-induced dietary alterations, can influence CD8+ T cell-mediated immunity. Defining the metabolic adaptations of CD8+ T cells in specific tissue environments informs our understanding of how these cells protect against pathogens and tumours and maintain tissue health at barrier sites. Here, we highlight recent findings revealing how metabolic networks enforce specific CD8+ T cell programmes and discuss how metabolism is integrated with CD8+ T cell differentiation and function and determined by environmental cues.

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Fig. 1: Organismal, niche and intrinsic metabolism dictate CD8+ T cell fate and function.
Fig. 2: Metabolism of CD8+ T cell activation and effector function.
Fig. 3: Metabolism of memory CD8+ T cell differentiation.
Fig. 4: Metabolism of tissue-resident memory CD8+ T cells.
Fig. 5: Metabolic insufficiency in chronic infection and cancer.

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Acknowledgements

M.R-C. is a Cancer Research Institute Irvington Fellow supported by the Cancer Research Institute (CRI2943), N.E.S is supported by the NCI Predoctoral to Postdoctoral Fellow Transition (F99/K00) Award (K00CA222711) and A.W.G. is supported by the NIH (AI067545, AI132122 and AI072117) and the University of California, San Diego Tata Chancellor Endowed Professorship. The authors thank L. Labarta-Bajo, A. Phan, M. Heeg, A. Ferry, K. Kennewick and A. Houk for insightful discussions and expert feedback on the manuscript.

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The authors contributed equally to all aspects of the article.

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Correspondence to Ananda W. Goldrath.

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M.R.-C. and N.E.S. declare no competing interests. A.W.G. serves on the scientific advisory boards of Pandion Therapeutics and Arsenal Bio.

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Nature Reviews Immunology thanks V. A. Boussiotis and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Glossary

ATP

The molecule of energy currency inside of cells; it is dephosphorylated to AMP and adenosine by CD73 and CD39, respectively, when in the extracellular space to suppress immune function.

Oxidative phosphorylation

Metabolic process in which mitochondrial processes of the electron transport chain make ATP by consuming oxygen, making carbon dioxide and water as metabolic by-products.

Glycolysis

Metabolic process of breaking down glucose for energy, with lactic acid as a metabolic by-product.

Carbon anabolism

Metabolic biosynthetic process building larger molecules from smaller molecules.

Anaplerosis

Metabolic reactions whose products replenish tricarboxylic acid cycle intermediates.

Tricarboxylic acid (TCA) cycle

Also called the Krebs cycle and the citric acid cycle, a metabolic process of breaking down acetyl-CoA to carbon intermediates for energy and for synthesizing new metabolic products.

mTOR complex 1

(mTORC1). A protein complex that integrates signals from oxygen, energy, nutrients, stress and growth factors to control the anabolic output of the cell by stimulating protein synthesis and anabolic metabolism and restraining autophagy under conditions of nutrient abundance.

Fatty acid synthesis

Metabolic process of building fatty acids from acetyl-CoA in the cell cytoplasm.

Sterol regulatory element-binding proteins

Transcription factors from the basic helix–loop–helix leucine zipper family that translocate to the nucleus when cellular sterol concentration is low to upregulate enzymes involved in sterol biosynthesis.

Electron transport chain

(ETC). Series of protein complexes in the mitochondria that uses proton gradients to drive ATP production.

Extracellular acidification rate

(ECAR). Real-time measurement of medium acidification, used to interpret cellular glycolysis.

Oxygen consumption rate

(OCR). Real-time measurement of oxygen in media, used to interpret mitochondrial and cellular respiration.

Spare respiratory capacity

The maximum capacity of a cell to consume oxygen once the mitochondrial membrane has been uncoupled.

Fatty acid oxidation

Mitochondrial process of breaking down fatty acids into acetyl-CoA derivatives for energy.

Fatty acid

A carboxylic acid with an unsaturated or a saturated aliphatic tail.

NADPH/NADP+ ratios

Nicotinamide adenine dinucleotide phosphate in its oxidized (NADP+) and reduced forms (NADPH). A cofactor used by all forms of cellular life, it has a key role in central antioxidant systems and anabolism.

mTORC2

A protein complex that senses growth factors to control survival, proliferation and cytoskeletal rearrangements.

NADH/NAD+ ratios

Nicotinamide adenine dinucleotide in its oxidized (NAD+) and reduced (NADH) forms. A cofactor found in all living cells that is involved in redox reactions for the generation of ATP.

Fatty acid-binding proteins

(FABPs). A family composed of 12 different isoforms with distinct stoichiometries, affinities and specificities for fatty acids and heterogenous expression among CD8+ T cell subsets.

Glutaminolysis

Metabolic process to break down glutamine for energy and for carbon products such as α-ketoglutarate.

Short-chain fatty acids

Carboxylic acids with a small hydrocarbon chain, usually derived from the diet or bacterial fermentation.

Immune recall

The ability of memory lymphocytes to mount an immune response to a previously encountered antigen. A diet in which the most energy is derived from fat, rather than sugar or protein.

High-fat diet

A diet in which the most energy is derived from fat, rather than sugar or protein.

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Reina-Campos, M., Scharping, N.E. & Goldrath, A.W. CD8+ T cell metabolism in infection and cancer. Nat Rev Immunol 21, 718–738 (2021). https://doi.org/10.1038/s41577-021-00537-8

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