Naive T cells are actively maintained in a quiescent state that promotes their survival and persistence. On antigen stimulation, T cells exit quiescence to initiate clonal expansion and effector differentiation. Initial studies focused on the immune receptors and transcriptional regulators involved in T cell quiescence and activation, but recent findings highlight cell metabolism as a crucial regulator of these processes. Here we summarize these intrinsic metabolic programmes and also describe how cell-extrinsic factors, such as nutrients and regulatory T cells, directly and indirectly balance quiescence and activation programmes in conventional T cells. We propose that immunological cues and nutrients license and tune metabolic programmes and signalling networks that communicate in a bidirectional manner to promote quiescence exit. Understanding the programmes that regulate T cell quiescence will be key for developing novel approaches to modulate protective and pathological T cell responses in human diseases.
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The authors acknowledge all investigators whose contributions they could not discuss owing to space limitations. Research in the Boothby and Chi laboratories was supported by funding from the US National Institutes of Health: AI113292 and HL106812 (M.R.B.), and AI105887, AI131703, AI140761, CA176624 and CA221290 (H.C.).
The authors declare no competing interests.
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A hyporesponsive state of T cells that occurs after receipt of antigen stimulation in the absence of appropriate costimulation.
- Aerobic glycolysis
A major metabolic pathway that supports biosynthetic and bioenergetic activities, in which glucose-derived pyruvate is converted into lactate in the presence of oxygen.
The glutaminase-dependent catalysis of glutamine, which supports anabolic metabolism.
- Oxidative phosphorylation
(OXPHOS). The oxidation of nutrients within mitochondria to generate ATP.
- One-carbon metabolism
A serine or glycine-dependent metabolic network, which centres around the folate cofactor, that regulates nucleotide synthesis, redox metabolism and methylation reactions.
- Tricarboxylic acid cycle
(TCA cycle). The metabolic pathway that converts acetyl-CoA derived from nutrients into ATP and carbon dioxide through oxidative phosphorylation.
- Mevalonate metabolism
An acetyl-CoA-dependent metabolic pathway that produces mevalonate to generate sterols and prenyl-group metabolites.
- Pentose phosphate pathway
(PPP). A metabolic pathway that generates five-carbon sugars and NAPDH necessary for nucleotide synthesis and other biosynthetic reactions.
- Tonic TCR signalling
Signalling downstream of T cell receptor recognition of self-peptide–MHC molecules.
- Asymmetric cell division
A cell division that generates two daughter cells with different fates, such as an effector T cell and a memory T cell.
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Chapman, N.M., Boothby, M.R. & Chi, H. Metabolic coordination of T cell quiescence and activation. Nat Rev Immunol 20, 55–70 (2020). https://doi.org/10.1038/s41577-019-0203-y
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