The metabolic state of T cells can provide a basis for categorizing diseases.
The opposing ends of an evolutionarily driven spectrum of T cell metabolic states are marked by the differences in metabolic demand and output between quiescent naive or memory cells and effector T cells.
Metabolic pathway use early after the re-activation of memory T cells is distinct from that of recently activated naive T cells as well as of mature effector T cells.
The organismal metabolic environment in obesity and diabetes influences T cell differentiation and is a risk factor for various autoimmune diseases.
Glucose, amino acid and lipid metabolism in pathogenic T cells are all potential targets for treating autoimmune diseases.
The cancer microenvironment enforces dysfunctional cellular metabolism in tumour-infiltrating lymphocytes, thereby negatively impacting their anticancer functionality.
In healthy individuals, metabolically quiescent T cells survey lymph nodes and peripheral tissues in search of cognate antigens. During infection, T cells that encounter cognate antigens are activated and — in a context-specific manner — proliferate and/or differentiate to become effector T cells. This process is accompanied by important changes in cellular metabolism (known as metabolic reprogramming). The magnitude and spectrum of metabolic reprogramming as it occurs in T cells in the context of acute infection ensure host survival. By contrast, altered T cell metabolism, and hence function, is also observed in various disease states, in which T cells actively contribute to pathology. In this Review, we introduce the idea that the spectrum of immune cell metabolic states can provide a basis for categorizing human diseases. Specifically, we first summarize the metabolic and interlinked signalling requirements of T cells responding to acute infection. We then discuss how metabolic reprogramming of T cells is linked to disease.
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G.K. is supported by the French Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer (ARC); Cancéropôle Ile-de-France; Institut National du Cancer (INCa); Institut Universitaire de France; Fondation pour la Recherche Médicale (FRM); the European Commission (ArtForce); the European Research Council (ERC); the LeDucq Foundation; the LabEx Immuno Oncology; the SIRIC Stratified Oncology Cell DNA Repair and Tumor Immune Elimination (SOCRATE); the SIRIC Cancer Research and Personalized Medicine (CARPEM); and the Paris Alliance of Cancer Research Institutes (PACRI). L.G. is supported by an intramural startup from the Department of Radiation Oncology of Weill Cornell Medical College (New York, USA), and by Sotio a.c. (Prague, Czech Republic). C.H. acknowledges funding from the following grants: Swiss National Science Foundation (SNSF) 310030_153059, 31003A_172848 and CRSII3_160766; and grant no. GRS-058/14 from the Gebert Rüf Foundation.
The authors declare no competing financial interests.
- T follicular helper (TFH) cells
A T cell subset that is specialized in providing help to B cells, reflecting a fundamental aspect of adaptive immunity and the generation of immunological memory.
The process of replenishing metabolic intermediates that have been used as substrates for a biosynthetic reaction (that is, cataplerosis).
- Malate–aspartate shuttle
A biochemical system in which malate carries reducing equivalents generated in the cytoplasm in the form of NADH across the inner membrane of the mitochondrion — which is impermeable to NADH — for oxidative phosphorylation.
- One-carbon metabolism
A bicyclic pathway that circulates carbon units from different amino acids — by coupling of the folate cycle to the methionine cycle — and from which carbon units are transferred to metabolic pathways essential to cellular growth and proliferation.
- M1 macrophages
Classically activated, pro-inflammatory macrophages that express transcription factors such as IRF5, NF-κB, AP-1 and STAT1 (as opposed to immunomodulatory, pro-fibrotic M2-spectrum macrophages).
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Bantug, G., Galluzzi, L., Kroemer, G. et al. The spectrum of T cell metabolism in health and disease. Nat Rev Immunol 18, 19–34 (2018). https://doi.org/10.1038/nri.2017.99
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