The metabolic life and times of a T‐cell
Open accessAbstract
Summary: The regulation of lymphocyte homeostasis is critical for the development and formation of productive immune responses. Cell numbers must be maintained to allow sufficient numbers of lymphocytes to combat foreign pathogens but prevent the accumulation of excess lymphocytes that may increase the risk of developing autoimmunity or neoplasia. Cell extrinsic growth factors are essential to maintain homeostasis and cell survival, and it has become increasingly apparent that a key mechanism of this control is through regulation of cell metabolism. The metabolic state of T cells can have profound influences on cell growth and survival and even differentiation. In particular, resting T cells utilize an energy efficient oxidative metabolism but shift to a highly glycolytic metabolism when stimulated to grow and proliferate by pathogen encounter. After antigen clearance, T cells must return to a more quiescent oxidative metabolism to support T‐cell memory. This review highlights how these metabolic changes may be intricately involved with both T‐cell growth and death in the control of homeostasis and immunity.
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Metabolism is centrally important in regulating T cell function.
“there has been an increasing understanding of the central importance of metabolism in regulating T cell function [5, 106, 107].”
From Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function (2013) · cites this paper as [107]
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“Although most investigation has centered on the signal transduction pathways that promote transcriptional activation of effector and cell growth genes, it has become apparent that cell metabolism must also play a critical role in immunity to permit transcriptional programs of highly energetic processes of cell growth,…”
BackgroundGlucose Availability Regulates IFN-γ Production and p70S6 Kinase Activation in CD8+ Effector T Cells
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“Multiple studies demonstrate that despite the presence of alternative metabolic fuels, limiting glucose metabolism in activated T cells results in decreased T-cell proliferation, deficient production of the effector cytokine interferon-c (IFNc), and the induction and activation of proapoptotic Bcl-2 family proteins su…”
BackgroundInfluentialRevving the Engine: Signal Transduction Fuels T Cell Activation
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“In particular, T cells cannot uptake cystine and require the reductive activity of APCs to provide the oxidized form of cystine, cysteine, to allow intracellular transport of this essential amino acid (16, 93, 94).”
BackgroundInfluentialT cell costimulation by chemokine receptors
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The serine/threonine kinase Pim-2 is a transcriptionally regulated apoptotic inhibitorPreprint
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“In response to IL-7, both STAT5a and STAT5b can induce the expression of Pim kinases, which in turn can promote glycolysis (71).”
BackgroundInterleukin 15 Controls both Proliferation and Survival of a Subset of Memory-Phenotype CD8+ T Cells
Judge, A. D., Zhang, X. M., Fujii, H., Surh, C. D., & Sprent, J. (2002) · The Journal of Experimental Medicine · doi:10.1084/jem.20020772 · Cited by 331 · see citing works
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“TCR signals can also activate the adenosine monophosphate (AMP)-activated protein kinase (AMPK) (49), which can also promote glucose uptake and oxidation in a manner consistent with the metabolism of resting T cells (50, 51).”
BackgroundResultTamás, P., Hawley, S. A., Clarke, R. G., Mustard, K. J., Green, K., Hardie, D. G., & Cantrell, D. A. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20052469 · Cited by 328 · cited 7× · see citing works
“TCR signals can also activate the adenosine monophosphate (AMP)-activated protein kinase (AMPK) (49), which can also promote glucose uptake and oxidation in a manner consistent with the metabolism of resting T cells (50, 51).”
BackgroundResultInfluentialPlas, D. R., Talapatra, S., Edinger, A. L., Rathmell, J. C., & Thompson, C. B. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m010551200 · Cited by 308 · see citing works
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“Multiple studies demonstrate that despite the presence of alternative metabolic fuels, limiting glucose metabolism in activated T cells results in decreased T-cell proliferation, deficient production of the effector cytokine interferon-c (IFNc), and the induction and activation of proapoptotic Bcl-2 family proteins su…”
BackgroundInfluentialDeficiency in Bak and Bax perturbs thymic selection and lymphoid homeostasis
Rathmell, J. C., Lindsten, T., Zong, W., Cinalli, R. M., & Thompson, C. B. (2002) · Nature Immunology · doi:10.1038/ni834 · Cited by 297 · cited 3× · see citing works
“Blatt NB, Boitano AE, Lyssiotis CA, Opipari AW Jr, Glick GD. Bz-423 superoxide signals B cell apoptosis via Mcl-1, Bak, and Bax.”
BackgroundSelf-citationBarnes, K., Ingram, J. C., Porras, O. H., Barros, L. F., Hudson, E. R., Fryer, L. G. D., Foufelle, F., Carling, D., Hardie, D. G., & Baldwin, S. A. (2002) · Journal of Cell Science · doi:10.1242/jcs.115.11.2433 · Cited by 289 · see citing works
Anergic T Cells Are Metabolically Anergic
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“In addition, failure to obtain sufficient nutrients may lead to T-cell anergy and an inability to respond to mitogenic signals (80).”
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“(142) found a role for Fas and Bim following chronic MHV infection.”
BackgroundHomeostasis of αβ TCR+ T cells
Marrack, P., Bender, J., Hildeman, D. A., Jordan, M. B., Mitchell, T., Murakami, M., Sakamoto, A., Schaefer, B. C., Swanson, B., & Kappler, J. W. (2000) · Nature Immunology · doi:10.1038/77778 · Cited by 245 · see citing works
Cutaneous lymphoproliferation and lymphomas in interleukin 7 transgenic mice.
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“Conversely, transgenic overexpression of IL-7 can increase T-cell numbers, demonstrating that it is a limiting component of homeostatic regulation of T-cell survival (57, 58).”
BackgroundPellegrini, M., Belz, G. T., Bouillet, P., & Strasser, A. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2336198100 · Cited by 238 · cited 4× · see citing works
“Indeed, resting T cells accumulate in Bim ⁄ ) animals (62, 63) and Bim ⁄ ) T cells can persist long-term following an immune response and accumulate as memory T cells (37, 125, 126).”
BackgroundInfluentialErlacher, M., Labi, V., Manzl, C., Böck, G., Tzankov, A., Häcker, G. A., Michalak, E. M., Strasser, A., & Villunger, A. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20061552 · Cited by 233 · cited 1× · see citing works
“Puma ⁄ Bim ⁄ ) T cells have synergistic resistance to cell death stimuli, indicating a non-redundant role for Puma in contributing to programmed cell death (131).”
BackgroundPallard, C., Stegmann, A. P. A., van Kleffens, T., Smart, F. M., Venkitaraman, A. R., & Spits, H. (1999) · Immunity · doi:10.1016/s1074-7613(00)80052-7 · Cited by 203 · cited 2× · see citing works
“Similarly, IL-7 signaling promotes Akt1 ⁄2 kinase activation, known regulators of glucose uptake and metabolism (70).”
BackgroundRathmell, J. C., Elstrom, R., Cinalli, R. M., & Thompson, C. B. (2003) · European Journal of Immunology · doi:10.1002/eji.200324048 · Cited by 197 · cited 2× · see citing works
“Conversely, metabolic excess may prevent apoptosis, exacerbate cell function, and potentially lead to inflammatory diseases (1, 4).”
BackgroundSelf-citationA novel inhibitor of glucose uptake sensitizes cells to FAS-induced cell death
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“In addition, to death receptor-mediated influence over DCs and antigen presentation, decreased glucose metabolism in T cells after antigen clearance may also enhance T-cell sensitivity to death receptor signaling, as inhibition of glucose metabolism can lead to increased apoptosis in response to Fas (136, 143).”
BackgroundInfluentialValmori, D., Tosello, V., Souleimanian, N. E., Godefroy, E., Scotto, L., Wang, Y., & Ayyoub, M. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.2.944 · Cited by 196 · see citing works
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“(141) found that compound mutants of Bim and Fas dramatically increased numbers of memory T-cell in the lymph node following an acute LCMV infection.”
BackgroundSelf-citationCeramide starves cells to death by downregulating nutrient transporter proteins
Guenther, G., Peralta, E. R., Rosales, K. R., Wong, S. Y., Siskind, L. J., & Edinger, A. L. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0802781105 · Cited by 194 · cited 1× · see citing works
“RNAi of Glut1 in lymphoid cell lines can decrease proliferation and glucose limitation can cause cell cycle arrest or apoptosis (2, 85, 86).”
BackgroundZhao, Y., Altman, B. J., Coloff, J. L., Herman, C. E., Jacobs, S. R., Wieman, H. L., Wofford, J. A., DiMascio, L. N., Ilkayeva, O., Kelekar, A., et al. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00153-07 · Cited by 193 · see citing works
Self-citationObservations on the Proliferation of Human Leucocytes Cultured with Phytohaemagglutinin
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“Although T-cell activation induces a rapid elevation in mitochondrial metabolism and oxygen consumption (15, 41), the most dramatic metabolic change is due to a sharp rise in glycolysis that results in a significant increase in the production of lactate (1, 9, 75, 76).”
BackgroundGenerating intrathymic microenvironments to establish T-cell tolerance
Anderson, G., Lane, P. J. L., & Jenkinson, E. J. (2007) · Nature reviews. Immunology · doi:10.1038/nri2187 · Cited by 186 · cited 1× · see citing works
“Upon entry into the peripheral pool of lymphocytes, the initial primary function of conventional T cells is surveillance (13, 14).”
BackgroundA mouse model for Glut-1 haploinsufficiency
Wang, D., Pascual, J. M., Yang, H., Engelstad, K., Mao, X., Cheng, J., Yoo, J. H., Noebels, J. L., & Vivo, D. C. D. (2006) · Human Molecular Genetics · doi:10.1093/hmg/ddl032 · Cited by 185 · cited 1× · see citing works
“Glut1 knockout animals are early embryonic lethal (84), and conditional Glut1 knockouts have not yet been described.”
BackgroundAlves, N. L., Derks, I. A. M., Berk, E., Spijker, R., van Lier, R. A. W., & Eldering, E. (2006) · Immunity · doi:10.1016/j.immuni.2006.03.018 · Cited by 179 · cited 9× · see citing works
“Multiple studies demonstrate that despite the presence of alternative metabolic fuels, limiting glucose metabolism in activated T cells results in decreased T-cell proliferation, deficient production of the effector cytokine interferon-c (IFNc), and the induction and activation of proapoptotic Bcl-2 family proteins su…”
BackgroundInfluentialIL-7 Is Essential for Homeostatic Control of T Cell Metabolism In Vivo
Jacobs, S. R., Michalek, R. D., & Rathmell, J. C. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0902593 · Cited by 177 · cited 1× · see citing works
“have recently demonstrated that naive T cells are unable to maintain glycolysis in vivo in the absence of IL-7 (67).”
BackgroundSelf-citationAerobic glycolysis and lymphocyte transformation
Hume, D. A., Radik, J., Ferber, E., & Weidemann, M. J. (1978) · Biochemical Journal · doi:10.1042/bj1740703 · Cited by 172 · cited 2× · see citing works
“Although T-cell activation induces a rapid elevation in mitochondrial metabolism and oxygen consumption (15, 41), the most dramatic metabolic change is due to a sharp rise in glycolysis that results in a significant increase in the production of lactate (1, 9, 75, 76).”
BackgroundNumerical and functional deficiency in T helper cells in protein energy malnutrition.
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Chang, W., Yang, K. D., Chuang, H., Jan, J.-T., & Shaio, M. (2002) · Clinical Immunology · doi:10.1006/clim.2002.5257 · Cited by 160 · cited 1× · see citing works
“The amino acid glutamine is also critical for T-cell metabolism and function, although as a mitochondrial fuel in addition to its role as an essential protein building block (98, 99).”
BackgroundProgramming, demarcating, and manipulating CD8+ T‐cell memory
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“To restore immune homeostasis, approximately 90% of these effector cells undergo a process of apoptosis or programmed cell death (6, 34), which ensures that the lymphocyte pool remains diverse (112).”
BackgroundThe adaptive response of the immune system to the particular malnutrition of eating disorders
Nova, E., Samartı́n, S., Gómez, S., Morandé, G., & Marcos, A. (2002) · European Journal of Clinical Nutrition · doi:10.1038/sj.ejcn.1601482 · Cited by 150 · cited 1× · see citing works
“Indeed, it has long been appreciated that malnutrition is associated with atrophy of lymphoid organs and a consequent increase in susceptibility to opportunistic infections (3, 32, 33).”
BackgroundSignaling Takes a Breath – New Quantitative Perspectives on Bioenergetics and Signal Transduction
Krauss, S., Brand, M. D., & Buttgereit, F. (2001) · Immunity · doi:10.1016/s1074-7613(01)00205-9 · Cited by 147 · cited 2× · see citing works
“These physiologic processes have specific metabolic needs that are largely supplied by efficient generation of adenosine triphosphate (ATP) as an energy source and modest levels of biosynthetic precursors for cell maintenance (15).”
BackgroundPradelli, L. A., Bénéteau, M., Chauvin, C., Jacquin, M. A., Marchetti, S., Muñoz‐Pinedo, C., Auberger, P., Pende, M., & Ricci, J. (2009) · Oncogene · doi:10.1038/onc.2009.448 · Cited by 144 · cited 14× · see citing works
“In addition, to death receptor-mediated influence over DCs and antigen presentation, decreased glucose metabolism in T cells after antigen clearance may also enhance T-cell sensitivity to death receptor signaling, as inhibition of glucose metabolism can lead to increased apoptosis in response to Fas (136, 143).”
BackgroundInfluentialDecreased Glucose Transporter Expression Triggers BAX-dependent Apoptosis in the Murine Blastocyst
Chi, M. M.-Y., Pingsterhaus, J. M., Carayannopoulos, M. O., & Moley, K. H. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m005508200 · Cited by 142 · see citing works
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“When T cells are treated with pertussis toxin to block chemokine receptor signaling, they fail to migrate into normal periarteriolar T-cell zones in secondary lymphoid organs and are deprived signals normally present in these areas (43, 44).”
BackgroundDistinct Regions of the Interleukin-7 Receptor Regulate Different Bcl2 Family Members
Jiang, Q., Li, W., Hofmeister, R., Young, H. A., Hodge, D. R., Keller, J. R., Khaled, A. R., & Durum, S. K. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.14.6501-6513.2004 · Cited by 139 · cited 1× · see citing works
“On the receptor, residue Tyr499 in the cytoplasmic domain is required for T-cell development (68, 69) and is necessary to activate both the Jak ⁄ signal transducer and activator of transcription 5 (STAT5) and PI3K ⁄ Akt pathways (7, 70).”
BackgroundFas (CD95) participates in peripheral T cell deletion and associated apoptosis in vivo
Mogil, R. J., Radvanyi, L. G., González‐Quintial, R., Miller, R. G., Mills, G. B., Theofilopoulos, A. N., & Green, D. R. (1995) · International Immunology · doi:10.1093/intimm/7.9.1451 · Cited by 136 · cited 1× · see citing works
“Although T-cell responses to peptide or Staphylococcus enterotoxin B (SEB) are abnormally enhanced and prolonged in Fas-deficient mice (140), the loss of Fas, tumor necrosis factor receptor 1 (TNFR1), or even both does not impede the death of T cells during shutdown of immune responses to acute HSV-1 infection (37).”
BackgroundMetabolic changes in activated T cells: An NMR study of human peripheral blood lymphocytes
Bental, M., & DEUTSCH, C. J. (1993) · Magnetic Resonance in Medicine · doi:10.1002/mrm.1910290307 · Cited by 136 · cited 1× · see citing works
“largely subsist using mitochondrial oxidative metabolism of glucose and glutamine with the bulk of metabolic precursors fully oxidized for maximal ATP generation (16, 17).”
BackgroundJohnson, K. M., Chen, X., Boitano, A. E., Swenson, L., Opipari, A. W., & Glick, G. D. (2005) · Chemistry & Biology · doi:10.1016/j.chembiol.2005.02.012 · Cited by 127 · see citing works
Edinger, A. L., Cinalli, R. M., & Thompson, C. B. (2003) · Developmental Cell · doi:10.1016/s1534-5807(03)00291-0 · Cited by 127 · cited 2× · see citing works
“ing T cells from utilizing extracellular glucose as a fuel (73, 88, 89).”
BackgroundLoss of Bim Increases T Cell Production and Function in Interleukin 7 Receptor–deficient Mice
Pellegrini, M., Bouillet, P., Robati, M., Belz, G. T., Davey, G. M., & Strasser, A. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20041328 · Cited by 127 · cited 2× · see citing works
“Indeed, resting T cells accumulate in Bim ⁄ ) animals (62, 63) and Bim ⁄ ) T cells can persist long-term following an immune response and accumulate as memory T cells (37, 125, 126).”
BackgroundT- and B-Cell Abnormalities in Systemic Lupus Erythematosus
Nagy, G., Koncz, Á., & Perl, A. (2005) · Critical Reviews in Immunology · doi:10.1615/critrevimmunol.v25.i2.30 · Cited by 123 · see citing works
Early effects of phytohaemagglutinin on glucose metabolism of normal human lymphocytes
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“stimulate increased glycolysis as an energy source (28, 29), provide fuel for the pentose phosphate pathways that produce pentose sugars required for nucleic acid synthesis and NADH for reducing power (30), and contribute to lipid synthesis (31).”
BackgroundBim mediates apoptosis of CD127lo effector T cells and limits T cell memory
Wojciechowski, S., Jordan, M. B., Zhu, Y., White, J., Zajac, A. J., & Hildeman, D. A. (2006) · European Journal of Immunology · doi:10.1002/eji.200635897 · Cited by 118 · cited 1× · see citing works
“Indeed, resting T cells accumulate in Bim ⁄ ) animals (62, 63) and Bim ⁄ ) T cells can persist long-term following an immune response and accumulate as memory T cells (37, 125, 126).”
BackgroundThe Requirement of Reversible Cysteine Sulfenic Acid Formation for T Cell Activation and Function
Michalek, R. D., Nelson, K. J., Holbrook, B. C., Yi, J. S., Stridiron, D., Daniel, L. W., Fetrow, J. S., King, S. B., Poole, L. B., & Grayson, J. M. (2007) · The Journal of Immunology · doi:10.4049/jimmunol.179.10.6456 · Cited by 112 · see citing works
Self-citationGlucose Metabolism Attenuates p53 and Puma-dependent Cell Death upon Growth Factor Deprivation
Zhao, Y., Coloff, J. L., Ferguson, E. C., Jacobs, S. R., Cui, K., & Rathmell, J. C. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m803580200 · Cited by 112 · cited 19× · see citing works
“Jeffers JR, et al. Puma is an essential mediator of p53-dependent and -independent apoptotic pathways.”
BackgroundInfluentialSelf-citationSuperantigen and endotoxin synergize in the induction of lethal shock
Blank, C. A., Luz, A., Bendigs, S., Erdmann, A. A., Wagner, H., & Heeg, K. (1997) · European Journal of Immunology · doi:10.1002/eji.1830270405 · Cited by 111 · cited 2× · see citing works
“A chief component of clonal contraction and generation of memory is the loss of antigenic and inflammatory signals after antigen or pathogen clearance (36).”
BackgroundmTOR: taking cues from the immune microenvironment
Delgoffe, G. M., & Powell, J. D. (2009) · Immunology · doi:10.1111/j.1365-2567.2009.03125.x · Cited by 110 · see citing works
Exploring regulatory mechanisms of CD8 + T cell contraction
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“Indeed, resting T cells accumulate in Bim ⁄ ) animals (62, 63) and Bim ⁄ ) T cells can persist long-term following an immune response and accumulate as memory T cells (37, 125, 126).”
BackgroundGrumont, R. J., Lock, P., Mollinari, M., Shannon, F. M., Moore, A., & Gerondakis, S. (2004) · Immunity · doi:10.1016/j.immuni.2004.06.004 · Cited by 106 · see citing works
Impaired CD8 T cell memory and CD4 T cell primary responses in IL-7Rα mutant mice
Osborne, L. C., Dhanji, S., Snow, J. W., Priatel, J. J., Ma, M. C., Miners, M. J., Teh, H., Goldsmith, M. A., & Abraham, N. B. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20061871 · Cited by 106 · cited 1× · see citing works
“On the receptor, residue Tyr499 in the cytoplasmic domain is required for T-cell development (68, 69) and is necessary to activate both the Jak ⁄ signal transducer and activator of transcription 5 (STAT5) and PI3K ⁄ Akt pathways (7, 70).”
BackgroundDifferential contribution of Puma and Noxa in dual regulation of p53‐mediated apoptotic pathways
Shibue, T., Suzuki, S., Okamoto, H., Yoshida, H., Ohba, Y., Takaoka, A., & Taniguchi, T. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601359 · Cited by 101 · cited 1× · see citing works
“Like Puma, Noxa is a p53 transcriptional target and can efficiently induce apoptosis (135).”
BackgroundBax Deficiency Partially Corrects Interleukin-7 Receptor α Deficiency
Khaled, A. R., Li, W., Huang, J., Fry, T. J., Khaled, A. S., Mackall, C. L., Muegge, K., Young, H. A., & Durum, S. K. (2002) · Immunity · doi:10.1016/s1074-7613(02)00450-8 · Cited by 93 · see citing works
Surviving the crash: Transitioning from effector to memory CD8+ T cell
D’Cruz, L. M., Rubinstein, M. P., & Goldrath, A. W. (2009) · Seminars in Immunology · doi:10.1016/j.smim.2009.02.002 · Cited by 88 · cited 2× · see citing works
“To restore immune homeostasis, approximately 90% of these effector cells undergo a process of apoptosis or programmed cell death (6, 34), which ensures that the lymphocyte pool remains diverse (112).”
BackgroundPhytohaemagglutinin stimulation of rat thymus lymphocyte glycolysis
Culvenor, J. G., & Weidemann, M. J. (1976) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/0304-4165(76)90005-2 · Cited by 88 · cited 1× · see citing works
“stimulate increased glycolysis as an energy source (28, 29), provide fuel for the pentose phosphate pathways that produce pentose sugars required for nucleic acid synthesis and NADH for reducing power (30), and contribute to lipid synthesis (31).”
BackgroundDevelopment of lymphocytes in interleukin 7‐transgenic mice
Samaridis, J., Casorati, G., Traunecker, A., Iglesias, A. H., Gutierrez, J. C., Müller, U., & Palacios, R. (1991) · European Journal of Immunology · doi:10.1002/eji.1830210230 · Cited by 86 · cited 1× · see citing works
“Conversely, transgenic overexpression of IL-7 can increase T-cell numbers, demonstrating that it is a limiting component of homeostatic regulation of T-cell survival (57, 58).”
BackgroundBarros, L. F., Young, M., Saklatvala, J., & Baldwin, S. A. (1997) · The Journal of Physiology · doi:10.1111/j.1469-7793.1997.517bd.x · Cited by 78 · cited 2× · see citing works
“Consistently, the MAPK pathway and Myc activation have been shown to play a role in Glut1 expression (48, 87) and may mediate the TCR-dependent control of Glut1.”
BackgroundAlexander‐Miller, M. A. (2004) · Immunologic Research · doi:10.1385/ir:31:1:13 · Cited by 72 · see citing works
Alterations in hexose monophosphate shunt during lymphoblastic transformation
Sagone, A. L., LoBuglio, A. F., & Balcerzak, S. P. (1974) · Cellular Immunology · doi:10.1016/0008-8749(74)90195-6 · Cited by 68 · cited 2× · see citing works
“Furthermore, this glycolytic program is reminiscent of the metabolism of many cancer cells (77) and allows T cells to rapidly supply their energy needs and increased intracellular glucose levels support the pentose phosphate pathways, which produce pentose sugars required for nucleic acid synthesis and NADPH for reduc…”
BackgroundBachmann, M. F., Gallimore, A., Jones, E., Ecabert, B., Acha‐Orbea, H., & Köpf, M. (2001) · European Journal of Immunology · doi:10.1002/1521-4141(200102)31:2 · Cited by 60 · see citing works
Fischer, S. F., Belz, G. T., & Strasser, A. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0706913105 · Cited by 59 · cited 1× · see citing works
“Puma also plays significant role in the death of antigen-specific CD8 T cells during an acute immune response and plays a physiological role during the shutdown of an immune response (130).”
BackgroundCronshaw, D. G., Owen, C. E., Brown, Z., & Ward, S. G. (2004) · The Journal of Immunology · doi:10.4049/jimmunol.172.12.7761 · Cited by 55 · see citing works
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“ing T cells from utilizing extracellular glucose as a fuel (73, 88, 89).”
BackgroundSelf-citationLoss of Mcl-1 Protein and Inhibition of Electron Transport Chain Together Induce Anoxic Cell Death
Brunelle, J. K., Shroff, E. H., Perlman, H., Strasser, A., Moraes, C. T., Flavell, R. A., Danial, N. N., Keith, B., Thompson, C. B., & Chandel, N. S. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.01535-06 · Cited by 41 · cited 1× · see citing works
“In addition, Mcl-1 is sensitive to changes in cell metabolism both at a level of protein translation as well as protein degradation (81, 136, 137).”
BackgroundThe effect of glutamine on murine splenic leukocyte responses to T and B cell mitogens
Griffiths, M., & Keast, D. (1990) · Immunology & Cell Biology · doi:10.1038/icb.1990.54 · Cited by 41 · cited 1× · see citing works
“The amino acid glutamine is also critical for T-cell metabolism and function, although as a mitochondrial fuel in addition to its role as an essential protein building block (98, 99).”
BackgroundNutrition, Immunity and Infections: T Lymphocyte Subpopulations in Protein--Energy Malnutrition
Özkan, H., Olgun, N., Sacmaz, E., Abacıoğlu, H., Okuyan, M., & Çevik, N. N. (1993) · Journal of Tropical Pediatrics · doi:10.1093/tropej/39.4.257 · Cited by 39 · cited 1× · see citing works
“Indeed, it has long been appreciated that malnutrition is associated with atrophy of lymphoid organs and a consequent increase in susceptibility to opportunistic infections (3, 32, 33).”
BackgroundEvidence for PI-3K-dependent migration of Th17-polarized cells in response to CCR2 and CCR6 agonists
Webb, A., Johnson, A., Fortunato, M., Platt, A., Crabbe, T., Christie, M. I., Watt, G. F., Ward, S. G., & Jopling, L. A. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.0408234 · Cited by 38 · see citing works
Organization of plasma membrane functional rafts upon T cell activation.
Tuosto, L., Parolini, I., Schröder, S., et al. (2001) · PubMed · doi:10.1002/1521-4141(200102)31:2<345::aid-immu345>3.0.co;2-l · Cited by 38 · see citing works
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“Although T-cell activation induces a rapid elevation in mitochondrial metabolism and oxygen consumption (15, 41), the most dramatic metabolic change is due to a sharp rise in glycolysis that results in a significant increase in the production of lactate (1, 9, 75, 76).”
BackgroundExpression of T‐cell receptor genes during early T‐cell development
Abbey, J. L., & O'Neill, H. C. (2007) · Immunology and Cell Biology · doi:10.1038/sj.icb.7100120 · Cited by 26 · cited 1× · see citing works
“Upon entry into the peripheral pool of lymphocytes, the initial primary function of conventional T cells is surveillance (13, 14).”
BackgroundCinalli, R. M., Herman, C. E., Lew, B. O., Wieman, H. L., Thompson, C. B., & Rathmell, J. C. (2005) · European Journal of Immunology · doi:10.1002/eji.200425729 · Cited by 19 · cited 3× · see citing works
“When T cells are treated with pertussis toxin to block chemokine receptor signaling, they fail to migrate into normal periarteriolar T-cell zones in secondary lymphoid organs and are deprived signals normally present in these areas (43, 44).”
BackgroundSelf-citationBz-423 superoxide signals B cell apoptosis via Mcl-1, Bak, and Bax
Blatt, N. B., Boitano, A. E., Lyssiotis, C. A., Opipari, A. W., & Glick, G. D. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.05.025 · Cited by 16 · see citing works
Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus
Gergely, P., Grossman, C., Niland, B., Puskas, F., Neupane, H., Allam, F., Banki, K., Phillips, P. E., & Perl, A. (2002) · Arthritis & Rheumatism · doi:10.1002/1529-0131(200201)46:1 · Cited by 5 · see citing works
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Human nutrition, the gut microbiome and the immune system
Kau, A. L., Ahern, P. P., Griffin, N. W., Goodman, A. L., & Gordon, J. I. (2011) · Nature · doi:10.1038/nature10213 · Cited by 2,588 · see citing works
CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer
McLane, L. M., Abdel-Hakeem, M. S., & Wherry, E. J. (2019) · Annual Review of Immunology · doi:10.1146/annurev-immunol-041015-055318 · Cited by 1,975 · see citing works
“Local availability of metabolic fuel sources and metabolites such as glucose, amino acids, and fatty acids may also have a role in exhaustion (197, 198).”
BackgroundTranscriptional control of effector and memory CD8+ T cell differentiation
Kaech, S. M., & Cui, W. (2012) · Nature Reviews Immunology · doi:10.1038/nri3307 · Cited by 1,628 · see citing works
The Science and Translation of Lactate Shuttle Theory
Brooks, G. A. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.03.008 · Cited by 1,486 · see citing works
“On one hand, T cell activation increases glycolysis and lactate accumulation due to low cellular mitochondrial content (Michalek and Rathmell, 2010), but on the other hand, lactate accumulation in the TME opposes T cell lactate efflux, leading to decreased cytokine production and cytotoxic activity…”
BackgroundImmunosenescence and Inflamm-Aging As Two Sides of the Same Coin: Friends or Foes?
Fulop, T., Larbi, A., Dupuis, G., Le Page, A., Frost, E. H., Cohen, A. A., Witkowski, J. M., & Franceschi, C. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01960 · Cited by 1,364 · see citing works
Metabolic Regulation of T Lymphocytes
MacIver, N. J., Michalek, R. D., & Rathmell, J. C. (2013) · Annual Review of Immunology · doi:10.1146/annurev-immunol-032712-095956 · Cited by 1,244 · see citing works
“Upon recognition of cognate antigen in the presence of self-MHC and costimulatory signals, T cells grow, proliferate, and ultimately differentiate into distinct subsets that possess unique roles in maintaining functional responses and regulating immune homeostasis (82).”
BackgroundSelf-citationCD8+ T Cells: Foot Soldiers of the Immune System
Zhang, N., & Bevan, M. J. (2011) · Immunity · doi:10.1016/j.immuni.2011.07.010 · Cited by 1,102 · see citing works
“Recently, it has been demonstrated that in addition to costimulatory signals, such as CD28-induced PI-3K-Akt-mTOR signaling (Michalek and Rathmell, 2010), TCR-ERK signaling is required for enhanced glycolysis and glucose plus glutamine uptake (Carr et al., 2010; Marko et al., 2010).”
InfluentialRegulation and function of mTOR signalling in T cell fate decisions
Chi, H. (2012) · Nature Reviews Immunology · doi:10.1038/nri3198 · Cited by 1,035 · see citing works
Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function
Sukumar, M., Liu, J., Ji, Y., Subramanian, M., Crompton, J. G., Yu, Z., Roychoudhuri, R., Palmer, D. C., Muranski, P., Karoly, E. D., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69589 · Cited by 952 · see citing works
Cancer Cell Metabolism: One Hallmark, Many Faces
Cantor, J. R., & Sabatini, D. M. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0345 · Cited by 945 · see citing works
“As mentioned above, cancer cells and normal proliferating cells share a similar collection of metabolic demands and adaptations (21, 30).”
BackgroundMetabolic targets for cancer therapy
Galluzzi, L., Kepp, O., Heiden, M. G. V., & Kroemer, G. (2013) · Nature Reviews Drug Discovery · doi:10.1038/nrd4145 · Cited by 705 · see citing works
The role of metabolism in the pathogenesis of osteoarthritis
Mobasheri, A., Rayman, M. P., Gualillo, O., Sellam, J., van der Kraan, P., & Fearon, U. (2017) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2017.50 · Cited by 742 · see citing works
San-Millán, I., & Brooks, G. A. (2016) · Carcinogenesis · doi:10.1093/carcin/bgw127 · Cited by 613 · see citing works
“When activated for cell growth and proliferation, T-cells switch to highly glycolytic activity (180) thus producing and exporting important amount of lactate through MCTs.”
BackgroundA two-way street: reciprocal regulation of metabolism and signalling
Wellen, K. E., & Thompson, C. B. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3305 · Cited by 528 · see citing works
Changes in Nutritional Status Impact Immune Cell Metabolism and Function
Alwarawrah, Y., Kiernan, K., & MacIver, N. J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01055 · Cited by 519 · see citing works
Cancer metabolism: current perspectives and future directions
Muñoz-Pinedo, C., El Mjiyad, N., & Ricci, J.-E. (2012) · Cell Death & Disease · doi:10.1038/cddis.2011.123 · Cited by 385 · see citing works
“during acute stimulation and cells exposed to growth factors.(4,5) Indeed, like cancer cells, these cells need to support high proliferation rates and thus require efficient”
BackgroundStaron, M. M., Gray, S. M., Marshall, H. D., Parish, I. A., Chen, J. H., Perry, C. J., Cui, G., Li, M. O., & Kaech, S. M. (2014) · Immunity · doi:10.1016/j.immuni.2014.10.013 · Cited by 384 · see citing works
“…receptors are of particular interest because they function in parallel pathways to control many aspects of T cell differentiation, proliferation, function, and survival (Finlay and Cantrell, 2011; Michalek and Rathmell, 2010; Pearce and Pearce, 2013; Powell and Delgoffe, 2010; Rao et al., 2010).”
BackgroundAcetate Promotes T Cell Effector Function during Glucose Restriction
Qiu, J., Villa, M., Sanin, D. E., Buck, M. D., O’Sullivan, D., Ching, R., Matsushita, M., Grzes, K. M., Winkler, F., Chang, C.-H., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.04.022 · Cited by 342 · see citing works
“T cells must acquire sufficient nutrients to engage the appropriate metabolism to support effector functions during infection and cancer (Buck et al., 2015, 2017; Buck et al., 2017; Chang et al., 2013; Michalek and Rathmell, 2010; O’Sullivan and Pearce, 2015; Pearce et al., 2013).”
BackgroundROS homeostasis and metabolism: a critical liaison for cancer therapy
Kim, J., Kim, J., & Bae, J. (2016) · Experimental & Molecular Medicine · doi:10.1038/emm.2016.119 · Cited by 295 · see citing works
IL-7 signaling and CD127 receptor regulation in the control of T cell homeostasis
Carrette, F., & Surh, C. D. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.04.010 · Cited by 257 · see citing works
“Besides being dependent on balanced pro- and anti-apoptotic signals, resting T cell survival is also dependent on their ability to maintain cellular metabolism, and particularly glucose metabolism [64].”
BackgroundBile acids and intestinal microbiota in autoimmune cholestatic liver diseases
Li, Y., Tang, R., Leung, P. S. C., Gershwin, M. E., & Ma, X. (2017) · Autoimmunity Reviews · doi:10.1016/j.autrev.2017.07.002 · Cited by 247 · see citing works
Chen, D., Tang, T.-X., Deng, H., Yang, X., & Tang, Z. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.747324 · Cited by 243 · see citing works
“In addition to dependence on a dynamic balance of proapoptotic and anti-apoptotic signals, it should be emphasized that the capacity of IL-7 to maintain steady metabolism— especially glucose metabolism—is also critical for T-cell survival (28).”
BackgroundThe liver kinase B1 is a central regulator of T cell development, activation, and metabolism
MacIver, N. J., Blagih, J., Saucillo, D. C., Tonelli, L., Griss, T., Rathmell, J. C., & Jones, R. G. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1100367 · Cited by 235 · see citing works
Self-citationMcNamee, E. N., Korns Johnson, D., Homann, D., & Clambey, E. T. (2013) · Immunologic Research · doi:10.1007/s12026-012-8349-8 · Cited by 234 · see citing works
“In recent years, there has been an increasing understanding of the central importance of metabolism in regulating T cell function [5, 106, 107].”
BackgroundDichloroacetate and cancer: New home for an orphan drug?
Kankotia, S., & Stacpoole, P. W. (2014) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2014.08.005 · Cited by 212 · see citing works
Qiao, G., Bucsek, M. J., Winder, N. M., Chen, M., Giridharan, T., Olejniczak, S. H., Hylander, B. L., & Repasky, E. A. (2018) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-018-2243-8 · Cited by 209 · see citing works
Sugar-free approaches to cancer cell killing
Mjiyad, N. E., Caro‐Maldonado, A., Ramírez‐Peinado, S., & Muñoz‐Pinedo, C. (2010) · Oncogene · doi:10.1038/onc.2010.466 · Cited by 195 · see citing works
“A high rate of glucose utilization is not exclusive of tumor cells, and other highly proliferative cells such as T lymphocytes also switch to aerobic glycolysis when stimulated to proliferate (Michalek and Rathmell, 2010).”
BackgroundLian, G., Gnanaprakasam, J. R., Wang, T., Wu, R., Chen, X., Liu, L., Shen, Y., Yang, M., Yang, J. J. J., Chen, Y., et al. (2018) · eLife · doi:10.7554/elife.36158 · Cited by 199 · see citing works
Metabolic Stress in Autophagy and Cell Death PathwaysPreprint
Altman, B. J., & Rathmell, J. C. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a008763 · Cited by 191 · see citing works
Self-citationTumor Microenvironment: A Metabolic Player that Shapes the Immune Response
Cassim, S., & Pouysségur, J. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms21010157 · Cited by 189 · see citing works
“T cells switch to a program of anabolic growth and biomass accumulation, which by definition dictates increased demand for ATP and metabolic resources to generate daughter cells.”
BackgroundInfluentialMetabolic reprogramming and metabolic dependency in T cells
Wang, R., & Green, D. R. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01155.x · Cited by 174 · see citing works
“The active T cell must acquire metabolic support for converting available metabolic resources into biomass, producing sufficient adenosine triphosphate (ATP) as a source of free energy (for thermodynamically unfavorable cellular processes), and finally, generating metabolic products as signals for triggering intra and…”
BackgroundReinforce the antitumor activity of CD 8 + T cells via glutamine restriction
Nabe, S., Yamada, T., Suzuki, J., Toriyama, K., Yasuoka, T., Kuwahara, M., Shiraishi, A., Takenaka, K., Yasukawa, M., & Yamashita, M. (2018) · Cancer Science · doi:10.1111/cas.13827 · Cited by 175 · see citing works
Palmer, C. S., Ostrowski, M., Gouillou, M., Tsai, L. M., Yu, D., Zhou, J., Henstridge, D. C., Maisa, A., Hearps, A. C., Lewin, S. R., et al. (2013) · AIDS · doi:10.1097/qad.0000000000000128 · Cited by 171 · see citing works
“Given the sustained energy requirements of activated T cells (as reviewed in references [18] and [25]) we hypothesized that T cells would up-regulate Glut1 expression and increase glucose transport in the context of HIV infection.”
BackgroundEpstein, T., Xu, L., Gillies, R. J., & Gatenby, R. A. (2014) · Cancer & Metabolism · doi:10.1186/2049-3002-2-7 · Cited by 160 · see citing works
“Consistent with this, aerobic glycolysis is observed in numerous physiological processes that are associated with acute membrane events such as lymphocyte proliferation and antibody secretion [3,7], macrophages migration [8], embryonic cytokinesis and cell migration [4].”
Gemta, L. F., Siska, P. J., Nelson, M. E., Gao, X., Liu, X., Locasale, J. W., Yagita∥, H., Slingluff, C. L., Hoehn, K. L., Rathmell, J. C., et al. (2019) · Science Immunology · doi:10.1126/sciimmunol.aap9520 · Cited by 155 · see citing works
Self-citationKouidhi, S., Elgaaïed, A. B., & Chouaı̈b, S. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00270 · Cited by 138 · see citing works
“To maintain a proper response, T-cell activation requires the upregulation of both glucose and amino acid transporters (1, 76).”
BackgroundRole of Polyamines in Immune Cell Functions
Hesterberg, R. S., Cleveland, J. L., & Epling‐Burnette, P. K. (2018) · Medical Sciences · doi:10.3390/medsci6010022 · Cited by 137 · see citing works
“Importantly, all of these cells must adjust their metabolic activity to meet functional demands that include migration, proliferation and sometimes long-lasting persistence in these diverse environments [5,6].”
BackgroundGlucose metabolism and metabolic flexibility in blood platelets
Aibibula, M., Naseem, K. M., & Sturmey, R. G. (2018) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.14274 · Cited by 132 · see citing works
“These data suggest that the functional responses were driven by choosing aerobic glycolysis over OXPHOS of glucose and glycogen consistent with a ‘Warburg’ or aerobic glycolytic phenotype (31,32).”
BackgroundtRNA-m1A modification promotes T cell expansion via efficient MYC protein synthesis
Liu, Y., Zhou, J., Li, X., Zhang, X., Shi, J., Wang, X., Li, H., Miao, S., He, X., He, X., et al. (2022) · Nature Immunology · doi:10.1038/s41590-022-01301-3 · Cited by 129 · see citing works
The RIG-I-like Receptor LGP2 Controls CD8+ T Cell Survival and Fitness
Suthar, M. S., Ramos, H. J., Brassil, M. M., Netland, J., Chappell, C. P., Blahnik, G., McMillan, A., Diamond, M., Clark, E. A., Bevan, M. J., et al. (2012) · Immunity · doi:10.1016/j.immuni.2012.07.004 · Cited by 126 · see citing works
“Both cell-intrinsic and -extrinsic apoptotic signaling pathways are important in regulating peripheral deletion of activated CD8+ T cells (Michalek and Rathmell, 2010).”
BackgroundDistinct metabolic programs in activated T cells: opportunities for selective immunomodulation
Wahl, D. R., Byersdorfer, C. A., Ferrara, J. L. M., Opipari, A. W., & Glick, G. D. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01148.x · Cited by 122 · see citing works
“More recent studies have observed a similar metabolic phenotype in unstimulated mouse and human T cells (7, 8), suggesting that the dependence on OXPHOS is a generalizable feature of resting lymphocyte populations (9).”
ResultModulation of T Cell Metabolism and Function through Calcium Signaling
Fracchia, K. M., Pai, C., & Walsh, C. M. (2013) · Frontiers in Immunology · doi:10.3389/fimmu.2013.00324 · Cited by 114 · see citing works
“Instead, it has been proposed that this switch is necessary to facilitate the rapid clonal expansion required to eliminate a microbial infection (45).”
BackgroundmTOR and metabolic pathways in T cell quiescence and functional activation
Yang, K., & Chi, H. (2012) · Seminars in Immunology · doi:10.1016/j.smim.2012.12.004 · Cited by 115 · see citing works
What Fuels Natural Killers? Metabolism and NK Cell Responses
Gardiner, C. M., & Finlay, D. K. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00367 · Cited by 113 · see citing works
MYC in Regulating Immunity: Metabolism and Beyond
Gnanaprakasam, J. R., & Wang, R. (2017) · Genes · doi:10.3390/genes8030088 · Cited by 106 · see citing works
Ananieva, E. A., Patel, C. H., Drake, C. H., Powell, J. D., & Hutson, S. M. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.554113 · Cited by 98 · see citing works
“These results are consistent with other reports (36) showing that during T cell activation, the T cells enhance utilization of amino acids to meet their increased metabolic, energy, and protein synthesis demands.”
BackgroundResultPiotrowski, J. T., Gomez, T. S., Schoon, R. A., Mangalam, A. K., & Billadeau, D. D. (2012) · Molecular and Cellular Biology · doi:10.1128/mcb.01288-12 · Cited by 100 · see citing works
“Finally, we investigated whether decreased GLUT1 on activated WASHout T cells affected glucose uptake since the primary form of metabolism in activated T cells is aerobic glycolysis (42), which is important for efficient T cell survival and proliferation (43, 44).”
BackgroundPrevite, D. M., O’Connor, E. C., Novak, E. A., Martins, C. P., Mollen, K. P., & Piganelli, J. D. (2017) · PLoS ONE · doi:10.1371/journal.pone.0175549 · Cited by 96 · see citing works
CD8 + T cell exhaustion in anti‐tumour immunity: The new insights for cancer immunotherapy
Huang, Y., Jia, A., Wang, Y., & Liu, G. (2022) · Immunology · doi:10.1111/imm.13588 · Cited by 95 · see citing works
“amino acids and fatty acids, may also play a role in exhaustion [60, 61].”
BackgroundChen, X., Sunkel, B. D., Wang, M., Kang, S., Wang, T., Gnanaprakasam, J. R., Liu, L., Cassel, T., Scott, D. A., Muñoz-Cabello, A. M., et al. (2022) · Science Immunology · doi:10.1126/sciimmunol.abm8161 · Cited by 93 · see citing works
“Beyond this, the availability of specific metabolites and the pathways that process them interconnect with signaling events and epigenetic regulators in the cell, orchestrating metabolic checkpoints that influence T cell activation, differentiation, and immune function (Birsoy et al., 2015; Chi, 2012; Gerriets and Rat…”
BackgroundMetabolism in the Tumor Microenvironment
Lau, A. N., & Heiden, M. G. V. (2019) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030419-033333 · Cited by 89 · see citing works
Wu, R., Chen, X., Kang, S., Wang, T., Gnanaprakasam, J. R., Yao, Y., Liu, L., Zheng, S. G., Fan, G., Burns, M. R., et al. (2020) · Science Advances · doi:10.1126/sciadv.abc4275 · Cited by 87 · see citing works
LKB 1 and AMPK : central regulators of lymphocyte metabolism and function
Blagih, J., Krawczyk, C. M., & Jones, R. G. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01157.x · Cited by 86 · see citing works
“In each phase of the immune response, T-cell metabolism must be matched to function to support T-cell survival, proliferation, and effector programs (4).”
BackgroundMacrophage proliferation, provenance, and plasticity in macroparasite infection
Rückerl, D., & Allen, J. E. (2014) · Immunological Reviews · doi:10.1111/imr.12221 · Cited by 84 · see citing works
Programmed necrosis and autophagy in immune function
Lu, J. V., & Walsh, C. M. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01147.x · Cited by 81 · see citing works
“As T cells switch from oxidative phosphorylation to an aerobic glycolytic metabolism following their activation through the TCR, they become less reliant on mitochondria for their source of energy (99).”
BackgroundChoileáin, S. N., Weyand, N. J., Neumann, C., Thomas, J., So, M., & Astier, A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0016287 · Cited by 75 · see citing works
“These include regulation of cell death [2] and autophagy [3], upregulation of negative signaling molecules such as CTLA-4 [4] and PD-1 [5], metabolic amino-acid regulation [6,7], control by T regulatory (Treg) cells [8] and Treg induction by dendritic cells [9], among many others.”
BackgroundNaseem, S., Hussain, T., & Manzoor, S. (2018) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2018.01.002 · Cited by 72 · see citing works
The relationship between CD4+ T cell glycolysis and their functions
Liu, S., Liao, S., Liang, L., Deng, J., & Zhou, Y. (2023) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2023.03.006 · Cited by 68 · see citing works
Perry, D. J., Yin, Y., Caza, T. N., Baker, H. V., Dozmorov, I. M., Perl, A., & Morel, L. M. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1200411 · Cited by 67 · see citing works
T-cell immunometabolism against cancer
Jiang, S., & Yan, W. (2016) · Cancer Letters · doi:10.1016/j.canlet.2016.09.003 · Cited by 64 · see citing works
Mitochondrial Retrograde Signalling and Metabolic Alterations in the Tumour Microenvironment
Yang, D., & Kim, J. (2019) · Cells · doi:10.3390/cells8030275 · Cited by 64 · see citing works
“They also differ across distinct cancers and are found even in non-transformed cells in the TME [21,22], indicating that metabolic flexibility can occur not only from genetic changes in genomic nDNA of cancer cells but also from modulation of metabolism by cells in the TME depending on the requirements of these cells…”
Peng, T., Zhu, J., Phasouk, K., Koelle, D. M., Wald, A., & Corey, L. (2012) · Journal of Virology · doi:10.1128/jvi.01237-12 · Cited by 63 · see citing works
“GLUT1, the primary glucose transporter in T lymphocytes, is transcriptionally expressed at low levels in resting T cells and both transcriptional induction and posttranslational trafficking are necessary for GLUT1-dependent glucose uptake during T-cell activation (6, 9), a process largely dependent on T-cell receptor…”
BackgroundNormal and cancer cell metabolism: lymphocytes and lymphoma
Altman, B. J., & Dang, C. V. (2012) · FEBS Journal · doi:10.1111/j.1742-4658.2012.08651.x · Cited by 62 · see citing works
Drivers of the Warburg Phenotype
Cairns, R. A. (2015) · The Cancer Journal · doi:10.1097/ppo.0000000000000106 · Cited by 60 · see citing works
“Workup to the present day, especially in T cells, has helped to define these metabolic changes in lymphocytes as they proliferate, differentiate, and adopt specific phenotypes.(17) It is now clear that a shift to a more glycolytic metabolism is required in order for T cells to proliferate in response to T-cell recepto…”
BackgroundExtracellular Lactate: A Novel Measure of T Cell Proliferation
Grist, J. T., Jarvis, L. B., Georgieva, Z. G., Thompson, S. A. J., Sandhu, H. K., Burling, K., Clarke, A., Jackson, S. E., Wills, M. R., Gallagher, F. A., et al. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1700886 · Cited by 59 · see citing works
“T cells have complex environment-dependent metabolic profiles, with different T cell subsets using different metabolic pathways to fuel their energy requirements (1, 2).”
BackgroundCalduch-Giner, J. À., Sitjà‐Bobadilla, A., & Pérez‐Sánchez, J. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00359 · Cited by 58 · see citing works
“Nutrient availability is also essential for the generation and maintenance of a protective effector immune system in humans and other model species (Fox et al., 2005; Michalek and Rathmell, 2010).”
BackgroundThe Effect of Malnutrition on Norovirus Infection
Hickman, D., Jones, M. K., Zhu, S., Roubidoux, E. K., Ostrov, D. A., Wang, X., Ukhanova, M., Sun, Y., Mai, V., Salemi, M., et al. (2014) · mBio · doi:10.1128/mbio.01032-13 · Cited by 56 · see citing works
Targeting T cell exhaustion: emerging strategies in non-small cell lung cancer
Liu, X., Xi, X., Xu, S., Chu, H., Hu, P., Li, D., Zhang, B., Liu, H., Jiang, T., & Lu, Z. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1507501 · Cited by 52 · see citing works
The role of complement in CD4+ T cell homeostasis and effector functions
Kolev, M. V., Friec, G. L., & Kemper, C. (2013) · Seminars in Immunology · doi:10.1016/j.smim.2013.04.012 · Cited by 50 · see citing works
Optically-Gated Self-Calibrating Nanosensors: Monitoring pH and Metabolic Activity of Living Cells
Peretz‐Soroka, H., Pevzner, A., Davidi, G., Naddaka, V. I., Tirosh, R., Flaxer, E., & Patolsky, F. (2013) · Nano Letters · doi:10.1021/nl401169k · Cited by 50 · see citing works
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“In addition, cellular proliferation, a central process of the lymphocyte response to antigen, is energetically taxing, and there is evidence suggesting that the metabolic pathways activated in T cells can influence not only sensitivity to apoptotic signals, but lineage decisions as well (58,59).”
BackgroundPromoting Thiol Expression Increases the Durability of Antitumor T-cell Functions
Kesarwani, P., Al-Khami, A. A., Scurti, G. M., Thyagarajan, K., Kaur, N., Husain, S., Fang, Q., Naga, O. S., Simms, P. E., Beeson, G. C., et al. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-1084 · Cited by 46 · see citing works
“While earlier reports have addressed the role of metabolism in T-cell activation and differentiation (12, 39, 40), its role in T-cell contraction and regulating antitumor response is beginning to be addressed (13, 41).”
MicroRNA-Mediated Restriction of HIV-1 in Resting CD4+ T Cells and Monocytes
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“Protein synthesis is also lower in resting cells [8], and overall a catabolic metabolism prevails, where ATP is generated from biosynthetic precursors like glucose via the TCA cycle and oxidative phosphorylation, supplying the minimum of energy needed to maintain housekeeping functions [23,24].”
BackgroundEarly Decision: Effector and Effector Memory T Cell Differentiation in Chronic Infection
Opata, M., & Stephens, R. (2013) · Current Immunology Reviews · doi:10.2174/1573395509666131126231209 · Cited by 42 · see citing works
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“Regarded as quiescent population, naïve andmemory T cells mainly rely on OXPHOS and fatty acid b-oxidation (FAO) to produce ATP and show reduced rates of nutrient uptake and biosynthesis (34, 35).”
BackgroundTerminating the immune response
Marrack, P., Scott-Browne, J. P., & MacLeod, M. K. L. (2010) · Immunological Reviews · doi:10.1111/j.1600-065x.2010.00928.x · Cited by 41 · see citing works
“the glucose receptor Glut1 on the cell surface, thus helping the T cells take up glucose to use as fuel to drive proliferation (28).”
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A critical role for Mnt in Myc-driven T-cell proliferation and oncogenesis
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Molecular Understanding of HIV-1 Latency
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“These lymphocytes persist as memory cells with different pattern of gene expression for the long-term survival and rapid response to the relevant antigen in the future [144, 145].”
BackgroundMetabolic Disorders in Multiple Myeloma
Gavriatopoulou, M., Paschou, S. Α., Ntanasis‐Stathopoulos, I., & Dimopoulos, M. A. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222111430 · Cited by 39 · see citing works
“Similarly, naïve and memory T cells mainly depend on OXPHOS and fatty acid β-oxidation (FAO) leading to ATP production [56,57].”
BackgroundQuantifying Biomass Changes of Single CD8+ T Cells during Antigen Specific Cytotoxicity
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“Studies have shown that TCR agonists such as anti-CD3 antibodies or compounds that cause cross-linking of CD3 proteins result in a rapid and maximal induction of Glut1 expression [24,25].”
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“Activated T cells transit their energy production from oxidative phosphorylation (OXPHOS) to glycolysis (Buck et al., 2015), and the ones that cannot fulfill this bioenergetic demand die by apoptosis (Michalek and Rathmell, 2010).”
BackgroundThe Ups and Downs of Metabolism during the Lifespan of a T Cell
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Epigenetic Control of Cdkn2a.Arf Protects Tumor-Infiltrating Lymphocytes from Metabolic Exhaustion
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“Loss of EZH2 function leads to metabolic exhaustion in CD8þ T cells T-cell activation leads to rapid and robust metabolic changes essential to support proliferation and function (35).”
BackgroundADP-dependent glucokinase regulates energy metabolism via ER-localized glucose sensing
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Autophagy in T‐cell differentiation, survival and memory
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“shifts from oxidative phosphorylation to glycolysis and increases its glucose consumption.(50) When the immune system has cleared the pathogen, most (approximate”
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“In contrast, regulatory T cells (Treg) and memory T cells (TMEM) have reduced glucose metabolism, mainly using lipid oxidation to promote inhibition and memory function [26, 27].”
BackgroundThe role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy
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“Frontiers in Immunology 05 acid transporters after activation (99).”
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Cereblon harnesses Myc-dependent bioenergetics and activity of CD8+ T lymphocytes
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“Activated immune cells are highly glycolytic [25,26] and infiltration of immune cells into the heart could contribute to changes in observed energy metabolism.”
Seeing the Warburg effect in the developing retina
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Coefficient of energy balance, a new parameter for basic investigation of the cerebrospinal fluid
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- Authors
- Michalek, R. D., & Rathmell, J. C.
- Affiliations
- Duke Medical Center (US)
- Corresponding author
- Rathmell, Jeffrey C.
- ORCID
- Rathmell, Jeffrey C.
- Venue
- Immunological Reviews
- Publisher
- Wiley
- Published
- 2010-06-15
- Volume
- 236
- Issue
- 1
- Pages
- 190-202
- ISSN
- 0105-2896 (ISSN-L)
- 1600-065X
- PMC
- PMC2983473
- OpenAlex
- W1672445637
- Cited by
- 186
- References
- 147
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 10 · 2023: 8 · 2022: 17 · 2021: 10 · 2020: 13 · 2019: 11 · 2018: 22 · 2017: 15 · 2016: 11 · 2015: 3 · 2014: 15 · 2013: 14 · 2012: 24
- FWCI
- 1.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Immunological Reviews (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (R01CA123350)
- National Institute of Allergy and Infectious Diseases (R01AI063345)
- 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
- T cell metabolism, lymphocyte homeostasis, oxidative phosphorylation, glycolysis, T cell quiescence, T cell proliferation, T cell differentiation, T cell memory, T cell death, cell survival, cell growth, autoimmunity, cancer
- MeSH terms
- Animals, Cell Survival, Homeostasis, Humans, Immunity, T-Lymphocytes, Time Factors, Apoptosis, Models, Immunological, Lymphocyte Count
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