Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development
Open accessAbstract
CD8(+) T cells undergo major metabolic changes upon activation, but how metabolism influences the establishment of long-lived memory T cells after infection remains a key question. We have shown here that CD8(+) memory T cells, but not CD8(+) T effector (Teff) cells, possessed substantial mitochondrial spare respiratory capacity (SRC). SRC is the extra capacity available in cells to produce energy in response to increased stress or work and as such is associated with cellular survival. We found that interleukin-15 (IL-15), a cytokine critical for CD8(+) memory T cells, regulated SRC and oxidative metabolism by promoting mitochondrial biogenesis and expression of carnitine palmitoyl transferase (CPT1a), a metabolic enzyme that controls the rate-limiting step to mitochondrial fatty acid oxidation (FAO). These results show how cytokines control the bioenergetic stability of memory T cells after infection by regulating mitochondrial metabolism.
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Memory CD8+ T cells (Tm) contain more mitochondria and have greater spare respiratory capacity, supported by fatty acid oxidation for ATP production.
“Tm cells display increased mitochondrial number and spare respiratory capacity, which is fueled by fatty acid oxidation to generate copious amount of ATP (Pearce et al., 2009; van der Windt et al., 2012).”
From Mitochondria in the Regulation of Innate and Adaptive Immunity (2015) · cites this paper as van der Windt et al., 2012
ACC2, CPT1A, acetyl-CoA, and malonyl-CoA are important players in memory T cell formation.
“Some important players to consider in this regard include acetyl-CoA carboxylase (ACC2) (21), the mitochondrial lipid transporter CPT1A (13, 22), and metabolites such as acetyl-CoA and malonyl-CoA (23).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [13]
IL-15 plays a key role in the catabolic switch of memory T cells by promoting mitochondrial biogenesis.
“The memory T cell–promoting cytokine interleukin (IL)–15 plays a key role in this catabolic switch by promoting mitochondrial biogenesis (13).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [13]
Memory T cells display increased mitochondrial mass, translating into greater spare respiratory capacity relative to naïve or effector T cells.
“However, TM cells also display a characteristic increase in mitochondrial mass, which translates into greater mitochondrial spare respiratory capacity (SRC) relative to naïve or TEFF populations (13).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [13]
Different subsets of T cells and different stages following T cell activation are characterized by the use of different metabolic pathways.
“Different subsets of T cells, as well as different stages following T cell activation, are characterized by the use of different metabolic pathways [97, 108, 109].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [109]
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- Authors
- van der Windt, G. J. W., Everts, B., Chang, C.-H., Curtis, J. D., Freitas, T. C., Amiel, E., Pearce, E. J., & Pearce, E. L.
- Affiliations
- Trudeau Institute (US)
- Corresponding author
- Pearce, Erika L.
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 36
- Issue
- 1
- Pages
- 68-78
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC3269311
- OpenAlex
- W1976714959
- Cited by
- 1,540
- References
- 49
- Citations by year
- 2026: 122 · 2025: 97 · 2024: 115 · 2023: 116 · 2022: 130 · 2021: 140 · 2020: 150 · 2019: 116 · 2018: 113 · 2017: 100 · 2016: 99 · 2015: 71 · 2014: 80 · 2013: 53 · 2012: 36
- FWCI
- 23.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Funders
- National Cancer Institute (R21CA158823)
- National Institute of Allergy and Infectious Diseases (R01AI091965)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- CD8+ T cell memory, T cell metabolism, IL-15, mitochondrial biogenesis, CPT1A, fatty acid oxidation, oxidative metabolism, effector T cells, T cell activation
- MeSH terms
- Animals, Carnitine O-Palmitoyltransferase, Fatty Acids, Flow Cytometry, Immunologic Memory, Mice, Inbred C57BL, Mitochondria, Models, Biological, Oxidation-Reduction, CD8-Positive T-Lymphocytes, Cell Respiration, Interleukin-15, Mice, Real-Time Polymerase Chain Reaction
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