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Cited by 1,363T-cell and B-cell ImmunologyCancer, Hypoxia, and MetabolismImmune cells in cancer

Fueling Immunity: Insights into Metabolism and Lymphocyte Function

Open access
Pearce, Erika L., Poffenberger, Maya C., Chang, Chih-Hao, Jones, Russell G.·2013·Science
DOI 10.1126/science.1242454PMC PMC4486656
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Abstract

Lymphocyte Metabolism: Lymphocytes are highly dynamic cells, undergoing extensive proliferation upon infection and then reducing in number upon pathogen clearance. Lymphocytes also circulate through many different tissue environments that vary in their nutrient and oxygen availability. Recent studies have revealed changes in metabolic programming that facilitate this dynamic behavior. How these changes occur and the specific effects that they have on lymphocyte function and on the ultimate outcome of an infection are not well understood. Pearce et al. ( 1242454 ) review recent progress in this area, suggest how parallels might be found in studying the metabolic changes seen in tumor cells, and propose challenges for the future.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that metabolic reprogramming is intricately linked to lymphocyte activation, differentiation, and function, drawing heavily on parallels with tumor cell metabolism. It highlights aerobic glycolysis, mitochondrial OXPHOS/ROS, amino acid and lipid pathways, metabolite signaling, and environmental nutrient/O₂ constraints as key determinants of T cell fate and effector responses.

Key findings

  • Resting naïve T cells maintain low glycolysis and rely on OXPHOS or fatty acid oxidation (FAO); upon TCR activation, T cells shift to aerobic glycolysis (the Warburg effect) while still engaging OXPHOS, and memory T cells return to a catabolic OXPHOS/FAO profile with increased mitochondrial mass and spare respiratory capacity.
  • Mitochondrial OXPHOS is also required for T cell activation: oligomycin blocks early activation markers and proliferation, mitochondrial ROS from complex III (Uqcrfs1) supports antigen-specific proliferation, and Ca²⁺ uptake drives TCA-cycle dehydrogenases, NADH, and ATP production.
  • Tumor metabolism informs T cell biology: the Warburg effect supplies biosynthetic intermediates; PKM2 M2 is less efficient at PEP-to-pyruvate conversion but supports anabolic flux; serine biosynthesis, glutaminolysis, and reductive carboxylation of α-KG under hypoxia are relevant; IDH1 mutations occur in ∼12% of glioblastoma multiforme and produce 2-hydroxyglutarate.
  • Metabolites act as signals: LKB1-AMPK senses adenylates and limits anabolic growth; α-KG-dependent dioxygenases are influenced by succinate, fumarate, and 2-HG; GAPDH can bind cytokine mRNA 3′UTRs and dampen IFN-γ translation when not engaged in glycolysis; standard culture media contain 25 mM glucose (five times blood glucose of 5 mM), 4 mM glutamine (eight times blood 0.5 mM), and 20% O₂ (two to four times blood/tissue levels).

Methods

  • Design: narrative review synthesizing published literature from immunology and cancer metabolism; no primary experiments or new data are reported.
  • Data/sample: cited studies on T cells, tumor cells, macrophages, dendritic cells, and B cells; no original sample or dataset.
  • Main analysis: conceptual integration of metabolic pathways, signaling, and gene regulation, with proposed models and hypotheses for T cell fate and function.

Limitations

  • The paper states technical challenges: metabolomics lacks a single global platform, cannot measure subcellular metabolite pools, measures steady-state levels rather than flux, and typically requires millions of cells, limiting analysis of rare T cell subsets.
  • The paper states that in vitro models are hyperglycemic and hyperoxic relative to in vivo conditions, potentially causing experimental variance between culture and animal models.
  • Evident from the text: as a narrative review, it does not use a systematic search or quantitative synthesis, and many proposed links (e.g., serine biosynthesis, reductive carboxylation, immunometabolites) are explicitly speculative and require future investigation.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1126/science.1242454

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 141 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    T cell metabolism changes dynamically with activation state.

    “Bioenergetic profiling of T cells has revealed that T cell metabolism changes dynamically with activation state (Fig. 1).”
    Quote in the paperSubstantial claim
  • Findingcitation

    Mitochondrial FAO stimulated downstream of TRAF6 is required for memory CD8+ T cell development.

    “We previously demonstrated that mitochondrial FAO stimulated downstream of TNF (tumor necrosis factor) receptor–associated factor 6 (TRAF6) is required for memory CD8+ T cell development (17).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Pearce EL Enhancing CD8 T-cell memory by modulating fatty acid metabolism Nature 2009 460 103 107 pmid: 19494812 19494812 PMC2803086 source

      Not checked in the free run.

  • Premisenone given

    Regulation of cellular metabolism is integrated into the T cell activation program.

    “Integrated into this program of activation is the regulation of cellular metabolism.”
    Quote in the paperSubstantial claim
  • Premisenone given

    Research on tumor cell metabolism has provided insight into metabolic pathways important for cell proliferation and the influence of metabolites on signal transduction and epigenetic programming.

    “Research on tumor cell metabolism has provided valuable insight into metabolic pathways important for cell proliferation and the influence of metabolites themselves on signal transduction and epigenetic programming.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    The predominant metabolic phenotype of activated T cells is a shift to aerobic glycolysis.

    “The predominant metabolic phenotype of activated T cells is a shift to aerobic glycolysis [reviewed in (11)].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [11] MacIver NJ Michalek RD Rathmell JC Metabolic regulation of T lymphocytes Annu. Rev. Immunol 2013 31 259 283 pmid: 23298210 23298210 PMC3606674 source

      Not checked in the free run.

  • May combine two claims. 44
  • Classified as probably not a substantial claim. 12

  • May combine two claims.

    Findingcitation

    Increased mitochondrial mass and spare respiratory capacity of memory T cells allows rapid mitochondrial ATP production upon TCR engagement, conferring a bioenergetic advantage upon secondary antigen exposure.

    “We have recently shown that increased mitochondrial mass and SRC of TM cells allows for rapid mitochondrial ATP production upon TCR engagement, conferring a bioenergetic advantage to TM cells upon secondary exposure to antigen (16).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] van der Windt GJ CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability Proc. Natl. Acad. Sci. U.S.A 2013 110 14336 14341 pmid: 23940348 23940348 PMC3761631 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Metabolic reprogramming and lymphocyte activation are intricately linked.

    “An emerging theme in immunology is that metabolic reprogramming and lymphocyte activation are intricately linked.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Aerobic glycolysis (the Warburg effect) is a common trait of actively proliferating cells.

    “This process, also known as the Warburg effect from earlier work in cancer biology, is a common trait of actively proliferating cells (5).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Vander Heiden MG Cantley LC Thompson CB Understanding the Warburg effect: The metabolic requirements of cell proliferation Science 2009 324 1029 1033 pmid: 19460998 19460998 PMC2849637 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    OXPHOS is still engaged in effector T cells, but lactate production from aerobic glycolysis is the dominant pathway of glucose metabolism in effector T cells.

    “It is important to note that OXPHOS is still engaged in TEFF cells (9); however, the production of lactate from pyruvate by aerobic glycolysis is the dominant pathway of glucose metabolism in TEFF cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Wang R The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation Immunity 2011 35 871 882 pmid: 22195744 22195744 PMC3248798 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    T cells deficient for Uqcrfs1 display impaired TCR-dependent ROS production and defects in antigen-specific proliferation.

    “T cells deficient for ubiquinol-cytochrome c reductase (Uqcrfs1), a component of complex III of the ETC, display impaired TCR-dependent ROS production and defects in antigen-specific proliferation (31).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Sena LA Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling Immunity 2013 38 225 236 pmid: 23415911 23415911 PMC3582741 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Restoring Ca2+ signals in Bax/Bak-null T cells restores mitochondrial ROS production and T cell proliferation.

    “Restoring Ca2+ signals in Bax/Bak-null T cells restores mitochondrial ROS production and T cell proliferation (33).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Jones RG The proapoptotic factors Bax and Bak regulate T Cell proliferation through control of endoplasmic reticulum Ca(2+) homeostasis Immunity 2007 27 268 280 pmid: 17692540 17692540 PMC2714273 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    AMPK activation and mTOR inhibition are potent activators of autophagy.

    “AMPK activation and mTOR inhibition are also both potent activators of autophagy, a catabolic process induced during starvation that promotes the degradation and recycling of cellular components [reviewed in detail in (24)].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Kundu M Thompson CB Autophagy: Basic principles and relevance to disease Annu. Rev. Pathol 2008 3 427 455 pmid: 18039129 18039129 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oligomycin blocks expression of early activation markers after TCR ligation and blunts subsequent T cell proliferation.

    “Oligomycin, a specific inhibitor of mitochondrial ATP synthase, can block the expression of early activation markers after TCR ligation and blunts subsequent T cell proliferation (27), suggesting that the naïve-to-effector transition requires either de novo production of ATP by mitochondria or specific signals generated during mitochondrial ATP production.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [27] Chang CH Posttranscriptional control of T cell effector function by aerobic glycolysis Cell 2013 153 1239 1251 pmid: 23746840 23746840 PMC3804311 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The naïve-to-effector transition requires either de novo production of ATP by mitochondria or specific signals generated during mitochondrial ATP production.

    “Oligomycin, a specific inhibitor of mitochondrial ATP synthase, can block the expression of early activation markers after TCR ligation and blunts subsequent T cell proliferation (27), suggesting that the naïve-to-effector transition requires either de novo production of ATP by mitochondria or specific signals generated during mitochondrial ATP production.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    T cells lacking Bax and Bak exhibit reduced Ca2+-dependent mitochondrial ROS production and T cell proliferation after TCR stimulation.

    “T cells lacking the apoptosis regulators Bax and Bak, which display defects in intracellular Ca2+ homeostasis, exhibit reduced Ca2+-dependent mitochondrial ROS production and T cell proliferation after TCR stimulation (33).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Jones RG The proapoptotic factors Bax and Bak regulate T Cell proliferation through control of endoplasmic reticulum Ca(2+) homeostasis Immunity 2007 27 268 280 pmid: 17692540 17692540 PMC2714273 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Proinflammatory CD4+ TH cells (TH1, TH2, TH17) display a strong bias toward glycolysis over mitochondrial metabolism, whereas induced CD4+ Treg cells display a mixed metabolism involving glycolysis, lipid oxidation, and OXPHOS.

    “This was first demonstrated by Michalek et al. (34), who determined that proinflammatory CD4+ T helper (TH) cells (TH1, TH2, and TH17 lineages) displayed a strong bias toward glycolysis over mitochondrial metabolism, whereas induced CD4+ T regulatory (Treg) lineage cells displayed a mixed metabolism involving glycolysis, lipid oxidation, and OXPHOS.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Michalek RD Cutting edge: Distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets J. Immunol 2011 186 3299 3303 pmid: 21317389 21317389 PMC3198034 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TH17 cell development is promoted by HIF-1α, which regulates glycolytic gene expression in TH17 cells.

    “TH17 cell development is promoted by hypoxia inducible factor–1α (HIF-1α) (35, 36), an oxygen-sensitive transcription factor that regulates glycolytic gene expression in TH17 cells.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Shi LZ HIF1a–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells J. Exp. Med 2011 208 1367 1376 pmid: 21708926 21708926 PMC3135370 source

      Not checked in the free run.

    • cites [36] Dang EV Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1 Cell 2011 146 772 784 pmid: 21871655 21871655 PMC3387678 source

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  • May combine two claims.

    Interpretationcitation

    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).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [21] Abu-Elheiga L Matzuk MM Abo-Hashema KA Wakil SJ Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2 Science 2001 291 2613 2616 pmid: 11283375 11283375 source

      Not checked in the free run.

    • cites [13] van der Windt GJ Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development Immunity 2012 36 68 78 pmid: 22206904 22206904 PMC3269311 source

      Not checked in the free run.

    • cites [22] DeBerardinis RJ Lum JJ Thompson CB Phosphatidylinositol 3-kinase-dependent modulation of carnitine palmitoyltransferase 1A expression regulates lipid metabolism during hematopoietic cell growth J. Biol. Chem 2006 281 37372 37380 pmid: 17030509 17030509 source

      Not checked in the free run.

    • cites [23] McGarry JD Mannaerts GP Foster DW A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis J. Clin. Invest 1977 60 265 270 pmid: 874089 874089 PMC372365 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Extracellular salt (NaCl) can influence TH17 homeostasis, and short-chain fatty acids can influence Treg homeostasis.

    “Added to this are recent results indicating that extracellular salt (NaCl) (37, 38) and short-chain fatty acids (39) can influence TH17 and Treg homeostasis, respectively.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [37] Wu C Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1 Nature 2013 496 513 517 pmid: 23467085 23467085 PMC3637879 source

      Not checked in the free run.

    • cites [38] Kleinewietfeld M Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells Nature 2013 496 518 522 pmid: 23467095 23467095 PMC3746493 source

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    • cites [39] Smith PM The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis Science 2013 341 569 573 pmid: 23828891 23828891 PMC3807819 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationcitation

    Glucose-dependent metabolic flux may help drive or reinforce T cell differentiation programs.

    “Glucose availability and acetyl-CoA production can also influence epigenetics by regulating the cytosolic acetyl-CoA pools available for histone acetylation reactions (51), raising the prospect that glucose-dependent metabolic flux may help drive or reinforce T cell differentiation programs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Inefficient cycling of this pathway would lead to cumulative depletion of mitochondrial OAA, collapse of TCA cycle, and disruption of mitochondrial function.

    “Inefficient cycling of this pathway would lead to cumulative depletion of mitochondrial OAA, leading to collapse of the TCA cycle and disruption of mitochondrial function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In this model, mitochondrial citrate is formed from oxaloacetate and acetyl-CoA, exported to cytosol, and converted back to acetyl-CoA by ATP citrate lyase (ACL).

    “In this model, mitochondrial citrate is formed from condensation of oxaloacetate and acetyl-CoA, after which citrate is exported from the mitochondrion to the cytosol and converted back to acetyl-CoA by ATP citrate lyase (ACL) (47).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Hatzivassiliou G ATP citrate lyase inhibition can suppress tumor cell growth Cancer Cell 2005 8 311 321 pmid: 16226706 16226706 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Research in cancer metabolism has increased understanding of metabolic requirements of proliferating cells and metabolic alterations that promote tumor growth.

    “Research in cancer metabolism over the past 10 years has increased our understanding of the metabolic requirements of proliferating cells, as well as the metabolic alterations that promote tumor growth.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Blocking glycolysis during TH17 cell differentiation reduces TH17 development and favors Treg formation.

    “Blocking glycolysis during TH17 cell differentiation reduced the development of TH17 cells and favored the formation of Tregs (35).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Shi LZ HIF1a–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells J. Exp. Med 2011 208 1367 1376 pmid: 21708926 21708926 PMC3135370 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationnone given

    Metabolism in T cells is likely regulated at several levels: TCR-mediated changes in metabolic gene expression, signal transduction downstream of cell surface receptors, and feedback inhibition/allosteric regulation.

    “Overall, metabolism in T cells is likely regulated at several levels: (i) TCR-mediated changes in the expression of metabolic genes facilitate the reprogramming required to match metabolic pathways to biological need; (ii) signal transduction downstream of cell surface receptors (i.e., costimulatory molecules and cytokine receptors) serve to fine-tune flux through these metabolic pathways; and (ii”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Rapid glucose processing promoted by the Warburg effect allows proliferating T cells to generate ATP quickly, and glycolysis generates metabolic intermediates important for cell growth and proliferation.

    “Rapid glucose processing promoted by the Warburg effect allows proliferating T cells to generate ATP quickly; glycolysis also generates metabolic intermediates important for cell growth and proliferation (Fig. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Acetyl-CoA has a central role in membrane biogenesis by providing two-carbon units for fatty acid and isoprenoid biosynthesis, and in protein prenylation and N-glycosylation.

    “Acetyl-CoA has a central role in membrane biogenesis because it provides two-carbon units for fatty acid and isoprenoid biosynthesis, as well as in other diverse processes such as protein prenylation and N-glycosylation (45).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [45] Wellen KE Thompson CB A two-way street: Reciprocal regulation of metabolism and signalling Nat. Rev. Mol. Cell Biol 2012 13 270 276 pmid: 22395772 22395772 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TCR/CD28 stimulation of T cells, surface immunoglobulin stimulation on B cells, and TLR stimulation of macrophages and DCs all promote changes in aerobic glycolysis characteristic of the Warburg effect.

    “TCR/CD28 stimulation of T cells (6), the stimulation of surface immunoglobulin on B cells (41), and TLR stimulation of macrophages and dendritic cells (DCs) (42, 43) all promote changes in aerobic glycolysis characteristic of the Warburg effect.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [6] Frauwirth KA The CD28 signaling pathway regulates glucose metabolism Immunity 2002 16 769 777 pmid: 12121659 12121659 source

      Not checked in the free run.

    • cites [41] Doughty CA Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: Role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth Blood 2006 107 4458 4465 pmid: 16449529 16449529 PMC1895797 source

      Not checked in the free run.

    • cites [42] Krawczyk CM Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation Blood 2010 115 4742 4749 pmid: 20351312 20351312 PMC2890190 source

      Not checked in the free run.

    • cites [43] Haschemi A The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism Cell Metab 2012 15 813 826 pmid: 22682222 22682222 PMC3370649 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted).

    Interpretationreasoning

    The metabolic microenvironment can influence T cell polarization.

    “This raises the intriguing possibility that the metabolic microenvironment (i.e., nutrient and oxygen availability) can influence T cell polarization (to be discussed later).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    PKM2 exists as inactive dimer or active tetramer, and oscillation between these states influences ability of cells to maintain anabolic metabolism.

    “PKM2 exists as either an inactive dimer or an active tetramer, and oscillation between these two states influences the ability of cells to maintain anabolic metabolism (56).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Anastasiou D Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis Nat. Chem. Biol 2012 8 839 847 pmid: 22922757 22922757 PMC3711671 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    PKM2 splice variant is expressed in embryonic tissues, proliferating cells, and tumor cells.

    “The muscle version of PK exists as one of two isoforms, M1 or M2, generated from differential splicing of the PKM primary mRNA transcript, with the PKM2 splice variant expressed in embryonic tissues, proliferating cells, and tumor cells (54).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Mazurek S Pyruvate kinase type M2: A key regulator of the metabolic budget system in tumor cells Int. J. Biochem. Cell Biol 2011 43 969 980 pmid: 20156581 20156581 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activating PKM2 with small-molecule agonists increases PEP-to-pyruvate conversion, reduces flux of glycolytic intermediates toward anabolic pathways, and slows tumor cell growth.

    “Activating PKM2 by using small-molecule agonists increases PEP-to-pyruvate conversion, reducing the flux of glycolytic intermediates toward anabolic pathways and slowing tumor cell growth (56, 60).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [56] Anastasiou D Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis Nat. Chem. Biol 2012 8 839 847 pmid: 22922757 22922757 PMC3711671 source

      Not checked in the free run.

    • cites [60] Kung C Small molecule activation of PKM2 in cancer cells induces serine auxotrophy Chem. Biol 2012 19 1187 1198 pmid: 22999886 22999886 PMC3775715 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    PKM2 possesses both protein and pyruvate kinase activities, with protein kinase activity using PEP as phosphate donor rather than ATP.

    “The phosphorylation of STAT3 by PKM2 demonstrates that PKM2 possesses both protein and pyruvate kinase activities, the former using PEP as a phosphate donor rather than ATP.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    The SBP may promote an alternate pathway of α-KG production for mitochondrial metabolism or promote the activity of α-KG-dependent enzymes.

    “Thus, the SBP may promote an alternate pathway of α-KG production for mitochondrial metabolism or promote the activity of α-KG– dependent enzymes (to be discussed later).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Increased PHGDH expression can promote enhanced serine biosynthesis and the proliferation of cancer cells.

    “Amplification of PHGDH has been observed in breast cancer and melanoma (65), and increased PHGDH expression can promote both enhanced serine biosynthesis and the proliferation of cancer cells (65, 66).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [65] Locasale JW Phosphoglycerate dehydrogenase diverts glycolytic flux and contributes to oncogenesis Nat. Genet 2011 43 869 874 pmid: 21804546 21804546 PMC3677549 source

      Not checked in the free run.

    • cites [66] Possemato R Functional genomics reveal that the serine synthesis pathway is essential in breast cancer Nature 2011 476 346 350 pmid: 21760589 21760589 PMC3353325 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationreasoning

    Protein kinase activity of PKM2 is predicted to be sensitive to metabolic flux, favored under high-glycolysis PEP conditions and antagonized by low-energy high-ADP concentrations.

    “The protein kinase activity of PKM2 (and any subsequent effects on STAT3 activity) would be predicted to be sensitive to metabolic flux, favored under high-glycolysis PEP conditions and antagonized by low-energy high-ADP concentrations.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Naïve T cells express both M1 and M2 PK isoforms at rest; mitogen-dependent activation promotes rapid accumulation of M2, which becomes dominant in effector T cells.

    “Naïve T cells express both M1 and M2 isoforms at rest; mitogen-dependent activation promotes the rapid accumulation of the M2 isoform, which becomes the dominant isoform expressed in TEFF cells (55).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Marjanovic S Eriksson I Nelson BD Expression of a new set of glycolytic isozymes in activated human peripheral lymphocytes Biochim. Biophys. Acta 1990 1087 1 6 pmid: 2169315 2169315 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Amino acids such as glutamine and leucine appear to play additional roles in T cell function beyond protein biosynthesis and may directly influence T cell activation by regulating metabolic reprogramming.

    “Thus, amino acids such as glutamine and leucine appear to play additional roles in T cell function beyond protein biosynthesis and may directly influence T cell activation by regulating metabolic reprogramming.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Tumor cells engineered to exclusively express M2 isoform display increased lactate production characteristic of Warburg effect and gain growth advantage in vivo over M1-expressing tumors.

    “Tumor cells engineered to exclusively express the M2 isoform display increased lactate production characteristic of the Warburg effect and gain a growth advantage in vivo over M1-expressing tumors (57).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [57] Christofk HR The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth Nature 2008 452 230 233 pmid: 18337823 18337823 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Tumor cells display a high degree of metabolic plasticity and can adapt their metabolism to support proliferation and viability under fluctuating environmental conditions.

    “One implication of this work is that tumor cells display a high degree of metabolic plasticity and can adapt their metabolism to support proliferation and viability under fluctuating environmental conditions.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Loss of LKB1-AMPK signaling promotes increased mTORC1 activity in both naïve and TEFF cells, which in turn facilitates production of the TH1 cytokine interferon-γ (IFN-γ) by TEFF cells.

    “Loss of LKB1-AMPK signaling promotes increased mTORC1 activity in both naïve and TEFF cells (88, 90), which in turn facilitates production of the TH1 cytokine interferon-γ (IFN-γ) by TEFF cells (88).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [88] MacIver NJ The liver kinase B1 is a central regulator of T cell development, activation, and metabolism J. Immunol 2011 187 4187 4198 pmid: 21930968 21930968 PMC3206094 source

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    • cites [90] Tamás P LKB1 is essential for the proliferation of T-cell progenitors and mature peripheral T cells Eur. J. Immunol 2010 40 242 253 pmid: 19830737 19830737 PMC2988414 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In mammalian cells, fluctuations in cellular energy are monitored by the heterotrimeric AMPK complex.

    “In mammalian cells, fluctuations in cellular energy are monitored by the heterotrimeric AMPK complex [reviewed in (83)].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Hardie DG Ross FA Hawley SA AMPK: A nutrient and energy sensor that maintains energy homeostasis Nat. Rev. Mol. Cell Biol 2012 13 251 262 pmid: 22436748 22436748 PMC5726489 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisenone given

    Together LKB1 and AMPK function as part of an evolutionarily conserved energy-sensing pathway that maintains cellular energy balance by promoting catabolic pathways of ATP production and limiting processes that consume ATP.

    “Together LKB1 and AMPK function as part of an evolutionarily conserved energy-sensing pathway that maintains cellular energy balance by promoting catabolic pathways of ATP production and limiting processes that consume ATP.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mutant IDH2 [Arg140→Gln140 (R140Q)] promotes α-KG depletion/2-HG production, promotes DNA hypermethylation in hematopoietic cells, and can inhibit myeloid differentiation when overexpressed in bone marrow stem cells.

    “Mutant IDH2 [Arg140→Gln140 (R140Q)], which promotes α-KG depletion/2-HG production, promotes DNA hypermethylation in hematopoietic cells and can inhibit myeloid differentiation when overexpressed in bone marrow stem cells (79).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [79] Figueroa ME Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation Cancer Cell 2010 18 553 567 pmid: 21130701 21130701 PMC4105845 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PHDs use O2 to hydroxylate HIF-1α on two conserved proline residues, facilitating their recognition by the E3 ubiquitin ligase VHL and promoting HIF-1α degradation by the proteosome.

    “PHDs use O2 to hydroxylate HIF-1α on two conserved proline residues, facilitating their recognition by the E3 ubiquitin ligase VHL and promoting HIF-1α degradation by the proteosome.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Although OXPHOS can support T cell survival and proliferation, only aerobic glycolysis can facilitate full effector status.

    “Thus although OXPHOS can support T cell survival and proliferation, only aerobic glycolysis can facilitate full effector status.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    GAPDH requires NAD+ for its enzymatic function, but NAD+ also interferes with mRNA binding, at least in vitro.

    “For example, GAPDH requires NAD+ for its enzymatic function, but NAD+ also interferes with mRNA binding, at least in vitro (112).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [112] Nagy E Identification of the NAD(+)-binding fold of glyceraldehyde-3-phosphate dehydrogenase as a novel RNA-binding domain. Biochem Biophys. Res. Commun 2000 275 253 260 pmid: 10964654 10964654 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Cancer cells harboring mutations in fumarate hydratase (FH) accumulate intracellular fumarate and display increased amounts of succinylated proteins.

    “Cancer cells harboring mutations in fumarate hydratase (FH), the TCA cycle enzyme that converts fumarate to malate, accumulate intracellular fumarate and display increased amounts of succinylated proteins (94).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [94] Bardella C Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status J. Pathol 2011 225 4 11 pmid: 21630274 21630274 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    2-HG acts as a competitive inhibitor of α-KG, and its production by mutant IDH1 consumes α-KG, leading to reduced TET2 and JmjC activity in tumor cells.

    “For example, 2-HG acts as a competitive inhibitor of α-KG, and its production by mutant IDH1 consumes α-KG (81, 99), leading to reduced TET2 and JmjC activity in tumor cells (79, 80).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [81] Xu W Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases Cancer Cell 2011 19 17 30 pmid: 21251613 21251613 PMC3229304 source

      Not checked in the free run.

    • cites [99] Ward PS The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate Cancer Cell 2010 17 225 234 pmid: 20171147 20171147 PMC2849316 source

      Not checked in the free run.

    • cites [79] Figueroa ME Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation Cancer Cell 2010 18 553 567 pmid: 21130701 21130701 PMC4105845 source

      Not checked in the free run.

    • cites [80] Lu C IDH mutation impairs histone demethylation and results in a block to cell differentiation Nature 2012 483 474 478 pmid: 22343901 22343901 PMC3478770 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When O2 availability is low, HIF-1α protein is stabilized because of reduced PHD activity, resulting in increased HIF-1α-dependent transcription.

    “When O2 availability is low, HIF-1α protein is stabilized because of reduced PHD activity, resulting in increased HIF-1α-dependent transcription (97).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Semenza GL Hypoxia-inducible factors in physiology and medicine Cell 2012 148 399 408 pmid: 22304911 22304911 PMC3437543 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activated T cells cultured in standard medium experience 25 mM glucose (five times standard blood glucose of 5 mM), 4 mM glutamine (eight times the standard concentration of 0.5 mM in blood), and 20% O2 [two to four times the oxygen tension in blood, which varies depending on tissue type].

    “Activated T cells cultured in standard medium (Iscove’s modified Dulbecco medium plus 10% serum) experience 25 mM glucose (five times standard blood glucose of 5 mM), 4 mM glutamine (eight times the standard concentration of 0.5 mM in blood), and 20% O2 [two to four times the oxygen tension in blood, which varies depending on tissue type (73)].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] McNamee EN Korns Johnson D Homann D Clambey ET Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function Immunol. Res 2013 55 58 70 pmid: 22961658 22961658 PMC3919451 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TEFF cells in the tumor microenvironment compete with tumor cells for available glucose, and this competition model of nutrient restriction limits the ability of TEFF cells to produce effector cytokines such as IFN-γ.

    “There is evidence that TEFF cells in the tumor microenvironment compete with tumor cells for available glucose, and this competition model of nutrient restriction limits the ability of TEFF cells to produce effector cytokines such as IFN-γ (27).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Chang CH Posttranscriptional control of T cell effector function by aerobic glycolysis Cell 2013 153 1239 1251 pmid: 23746840 23746840 PMC3804311 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    Gas chromatography coupled to MS (GC-MS) is effective at quantifying organic acids such as TCA cycle intermediates but not most glycolytic intermediates.

    “For example, gas chromatography coupled to MS (GC-MS) is effective at quantifying organic acids such as TCA cycle intermediates but not most glycolytic intermediates.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Metabolic and environmental influences on T cell function in vivo may elicit very different responses and may account for experimental variance between T cell responses in a petri dish versus what is observed in animal models.

    “Thus, metabolic and environmental influences on T cell function in vivo may elicit very different responses and may account for experimental variance between T cell responses in a petri dish versus what is observed in animal models.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Some tissue sites, such as the thymus, bone marrow, and the gastrointestinal epithelium, are naturally hypoxic, whereas inflammation can promote local hypoxic regions in tissues.

    “Some tissue sites, such as the thymus, bone marrow, and the gastrointestinal epithelium, are naturally hypoxic, whereas inflammation can promote local hypoxic regions in tissues (73).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] McNamee EN Korns Johnson D Homann D Clambey ET Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function Immunol. Res 2013 55 58 70 pmid: 22961658 22961658 PMC3919451 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Loss of HIF-1α impairs TH17 expansion and induction of experimental autoimmune encephalitis.

    “Loss of HIF-1α impairs TH17 expansion and induction of experimental autoimmune encephalitis (35)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Shi LZ HIF1a–dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells J. Exp. Med 2011 208 1367 1376 pmid: 21708926 21708926 PMC3135370 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Most in vitro assays to assess T cell function are performed at nutrient and O2 levels much higher than seen in normal physiology; these conditions model a hyperglycemic and hyperoxic environment never seen in vivo.

    “Most in vitro assays to assess T cell function are performed at nutrient and O2 levels much higher than seen in normal physiology; these conditions model a hyperglycemic and hyperoxic environment never seen in vivo.”
    Quote in the paperSubstantial claim
52 of 52

  • The paper relies on this without support.

    Upon activation, lymphocytes must meet increased bioenergetic and biosynthetic demands of proliferation and adapt to potentially limiting nutrients and oxygen.

    “Lymphocytes face major metabolic challenges upon activation. They must meet the bioenergetic and biosynthetic demands of increased cell proliferation and also adapt to changing environmental conditions, in which nutrients and oxygen may be limiting.”

  • The paper relies on this without support.

    The reasons T cells adopt specific metabolic programs and the impact of these programs on T cell function and immunological outcome are unclear.

    “However, why T cells adopt specific metabolic programs and the impact that these programs have on T cell function and, ultimately, immunological outcome remain unclear.”

  • The paper relies on this without support.

    Metabolic programming in tumor cells and proliferating T cells share certain similarities.

    “Given certain similarities between metabolic programming in tumor cells and proliferating T cells, it stands to reason that metabolites will participate in T cell signaling as well.”

  • The paper relies on this without support.

    Total abundance of α-KG is low in most cell types.

    “Additionally, total abundance of α-KG is low in most cell types.”

  • The authors state this as an assumption.

    Activated T cells frequently transition between nutrient-replete states (lymph nodes) and nutrient-deficient states (sites of infection).

    “If activated T cells frequently transition between nutrient-replete states (lymph nodes) and nutrient-deficient states (sites of infection), then management of metabolic resources is an important consideration for lymphocytes in order to ensure maintenance of proliferation and/or effector function.”

  • The paper relies on this without support.

    Interfering with metabolic pathways by using agents such as metformin and rapamycin has already revealed substantial and unexpected effects on T cell–mediated immunity.

    “Interfering with metabolic pathways by using agents such as metformin and rapamycin has already revealed substantial and unexpected effects on T cell– mediated immunity.”
6 of 6

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References 122 · Cited by 1,363

Authors
Pearce, E. L., Poffenberger, M. C., Chang, C.-H., & Jones, R. G.
Affiliations
  • Washington University in St. Louis (US)
  • McGill University (CA)
Corresponding author
  • Pearce, Erika L.
  • Jones, Russell G.
ORCID
Venue
Science
Publisher
American Association for the Advancement of Science (AAAS)
Published
2013-10-11
Volume
342
Issue
6155
Pages
1242454-1242454
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
DOI
10.1126/science.1242454
PMC
PMC4486656
OpenAlex
W1975566288
Semantic Scholar
518aa5b26772d6dcd1b09005f3af65a0ea6116c3
Cited by
1,363
References
122
Citations by year
2026: 92 · 2025: 87 · 2024: 127 · 2023: 120 · 2022: 119 · 2021: 135 · 2020: 121 · 2019: 104 · 2018: 116 · 2017: 102 · 2016: 95 · 2015: 88 · 2014: 55 · 2013: 2
FWCI
6.98
Type
journal article
Language
en
Open access
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
Funders
  • Arthritis Society
  • Canadian Institutes of Health Research (MOP-93 799)
  • National Cancer Institute (CA158823, R21CA158823, R01CA181125)
  • National Institute of Allergy and Infectious Diseases (R01AI091965, AI 091965)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
Keywords
lymphocyte metabolism, metabolic reprogramming, T cell activation, T cell proliferation, T cell fate, nutrient limitation, oxygen limitation, cancer metabolism, signal transduction, epigenetic programming, immunometabolism
MeSH terms
AMP-Activated Protein Kinase Kinases, Thyroid Hormone-Binding Proteins, Animals, Carrier Proteins, Cell Differentiation, Citric Acid Cycle, Gene Expression Regulation, Glycolysis, Humans, Ketoglutaric Acids, Lymphocyte Activation, Membrane Proteins, Mitochondria, Neoplasms, Protein Kinases, T-Lymphocytes, Thyroid Hormones, Protein Serine-Threonine Kinases, Cell Proliferation

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Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

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