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Metabolic control of innate-like T cells

Nature Reviews Immunology (2025)Cite this article

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Abstract

Immunometabolism, the intersection of cellular metabolism and immune function, has revolutionized our understanding of T cell biology. Changes in cellular metabolism help guide the development of thymocytes and the transition of T cells from naive to effector, memory and tissue-resident states. Innate-like T cells are a unique group of T cells with special characteristics. They respond rapidly, reside mainly in tissues and express T cell receptors with limited diversity that recognize non-peptide antigens. This group includes invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells and some populations of γδ T cells. Different subsets of innate-like T cells rely on specific metabolic pathways that influence their differentiation and function and distinguish them from conventional CD4+ and CD8+ T cells. Although there are differences between innate-like T cell types, they share metabolic and functional features. In this Review, we highlight recent research in this emerging field. Understanding how metabolic programmes differ between innate-like T cells and other T cells may open opportunities for tailoring innate-like T cell responses and adoptive T cell therapies for use in cancer, metabolic and autoimmune diseases.

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Fig. 1: Properties of innate-like T cells.
Fig. 2: Metabolic pathways in mouse iNKT cells.
Fig. 3: Metabolic pathways in human MAIT cells.
Fig. 4: Metabolic programmes of mouse γδ T cells and MAIT cells.

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Acknowledgements

The authors thank the Marga and Walter Boll foundation and the Virnich foundation for supporting their research, and acknowledge grants from the US National Institutes of Health (P30 DK120515, R01 AI172112) and a grant from Kyowa Kirin, Inc. (KKNA-Kyowa Kirin North America).

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Authors and Affiliations

  1. Faculty of Medicine and University Hospital Cologne, Clinic III for Internal Medicine, University of Cologne, Cologne, Germany

    Thomas Riffelmacher

  2. La Jolla Institute for Immunology, La Jolla, CA, USA

    Thomas Riffelmacher & Mitchell Kronenberg

  3. Department of Molecular Biology, University of California San Diego, La Jolla, CA, USA

    Mitchell Kronenberg

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Glossary

Dendritic epidermal T cells

A population of unique, dendritic-shaped γδ T cells expressing an invariant Vγ5Vδ1 T cell receptor (TCR). They are selected in the thymus during fetal development in a SKINT1-dependent manner and migrate to the skin epidermis, where they become long-lived, self-renewing immune sentinels that respond to stressed or damaged keratinocytes.

Fatty acid oxidation

(FAO; also known as β-oxidation). The catabolic process by which fatty acid molecules are broken down inside mitochondria to generate acetyl-coenzyme A (acetyl-CoA). Acetyl-CoA enters the tricarboxylic acid cycle (TCA cycle), generating NADH and FADH2, which are electron carriers used in the electron transport chain.

Glycolysis

A set of metabolic reactions that occur in the cytoplasm and convert glucose to pyruvate or lactate.

Innate-like T cells

(Also known as unconventional T cells). A special group of T cells that acquire effector functions in the thymus, provide rapid immune responses and are predominantly resident in tissues. They have invariant or semi-invariant T cell receptors (TCRs), and they recognize types of antigens that are different from the peptides presented by polymorphic MHC class I and class II proteins to conventional T cells.

Invariant natural killer T cells

(iNKT cells). An innate-like T cell subset that is a specialized lineage of T cells with invariant T cell receptor (TCR) α-chains. They recognize lipid antigens presented by CD1d molecules and rapidly produce cytokines. They play crucial roles in immune responses against infections and other contexts.

Mitochondrial membrane potential

An electric potential difference across the inner mitochondrial membrane that is crucial for ATP production. The potential drives protons back across the membrane through ATP synthase, enabling the phosphorylation of ADP to ATP. Changes in mitochondrial membrane potential are often indicators of mitochondrial activity, health and function, and can be used as a proxy for the mitochondrial energy status. A loss of mitochondrial membrane potential can indicate mitochondrial silencing, removal or dysfunction.

mTOR

The catalytic subunit of two structurally distinct complexes: mTORC1 and mTORC2. mTORC1 includes mTOR, RAPTOR, mLST8, PRAS40 and DEPTOR; it regulates cell growth and metabolism; and is inhibited by rapamycin. mTORC2 is composed of mTOR, RICTOR, mLST8, mSIN1, PROTOR1, PROTOR2 and DEPTOR; it controls cell survival and cytoskeletal organization; and is unaffected by rapamycin.

Mucosal-associated invariant T cells

(MAIT cells). An innate-like T cell subset characterized by their invariant T cell receptor (TCR) α-chain. They recognize vitamin B metabolites presented by MR1 protein. They may also recognize other antigens, such as sulfated cholesterol derivatives. They provide rapid responses that effect other cell types and are particularly frequent among human intrahepatic lymphocytes.

Oxidative phosphorylation

(OXPHOS). The mitochondrial pathway in which cells use enzymes to oxidize nutrients, thereby releasing chemical energy to produce ATP. It depends on the reducing agents NADH and FADH2 that are generated during the tricarboxylic acid cycle (TCA cycle) to build a proton gradient across the inner mitochondrial membrane. This mitochondrial membrane potential fuels the electron transfer chain that is coupled to the synthesis of ATP through this electrochemical transmembrane gradient.

Tricarboxylic acid cycle

(TCA cycle). A group of chemical reactions within mitochondria that help generate chemical energy in the form of ATP, which is provided by oxidizing the acetyl group of acetyl-coenzyme A (acetyl-CoA). The TCA cycle is involved in the metabolism of proteins, fats and carbohydrates.

γδ T cells

A population of T cells characterized by expression of T cell receptors (TCRs) encoded by gene families with a limited repertoire of V genes. Not all γδ T cells are innate-like T cells; for example, human Vδ1+ γδ T cells or Vγ9–Vδ2+ γδ T cells display unexpected parallels with conventional αβ T cells, whereas, Vγ9+Vδ2+ γδ T cells are more innate-like. γδ T cells are found in tissues and the blood, and the prevalence of different Vγ and Vδ genes varies according to the cellular location. They recognize a broad range of antigens, but responses to processed peptides presented by polymorphic MHC molecules are not typical. Butyrophilins play a role in the activation of several γδ T cell subsets.

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Riffelmacher, T., Kronenberg, M. Metabolic control of innate-like T cells. Nat Rev Immunol (2025). https://doi.org/10.1038/s41577-025-01219-5

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