Unraveling the Complex Interplay Between T Cell Metabolism and Function.

Metabolism drives function, on both an organismal and a cellular level. In T cell biology, metabolic remodeling is intrinsically linked to cellular development, activation, function, differentiation, and survival. After naive T cells are activated, increased demands for metabolic currency in the form of ATP, as well as biomass for cell growth, proliferation, and the production of effector molecules, are met by rewiring cellular metabolism. Consequently, pharmacological strategies are being developed to perturb or enhance selective metabolic processes that are skewed in immune-related pathologies. Here we review the most recent advances describing the metabolic changes that occur during the T cell lifecycle. We discuss how T cell metabolism can have profound effects on health and disease and where it might be a promising target to treat a variety of pathologies.

[1]  D. M. Smith,et al.  Regulatory T Cell Migration Is Dependent on Glucokinase-Mediated Glycolysis , 2018, Immunity.

[2]  R. Evans,et al.  Metabolic control of regulatory T cell (Treg) survival and function by Lkb1 , 2017, Proceedings of the National Academy of Sciences.

[3]  J. Liu,et al.  Oxidative stress controls regulatory T cell apoptosis and suppressor activity and PD-L1-blockade resistance in tumor , 2017, Nature Immunology.

[4]  Joerg M. Buescher,et al.  Mitochondrial Priming by CD28 , 2017, Cell.

[5]  E. Ma,et al.  AMPK Maintains Cellular Metabolic Homeostasis through Regulation of Mitochondrial Reactive Oxygen Species. , 2017, Cell reports.

[6]  B. Kwon,et al.  4-1BB signaling activates glucose and fatty acid metabolism to enhance CD8+ T cell proliferation , 2016, Cellular &Molecular Immunology.

[7]  Y. Zhang,et al.  Metabolic control of TH17 and induced Treg cell balance by an epigenetic mechanism , 2017, Nature.

[8]  Fatty Acid Uptake in T Cell Subsets Using a Quantum Dot Fatty Acid Conjugate , 2017, Scientific Reports.

[9]  E. Pearce,et al.  Ancillary Activity: Beyond Core Metabolism in Immune Cells. , 2017, Cell metabolism.

[10]  Sheng-Cai Lin,et al.  Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK , 2017, Nature.

[11]  P. Fink,et al.  Cutting Edge: Defective Aerobic Glycolysis Defines the Distinct Effector Function in Antigen-Activated CD8+ Recent Thymic Emigrants , 2017, The Journal of Immunology.

[12]  D. Wallace,et al.  Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments. , 2017, Cell metabolism.

[13]  S. Dimauro,et al.  Cytochrome c Oxidase Activity Is a Metabolic Checkpoint that Regulates Cell Fate Decisions During T Cell Activation and Differentiation. , 2017, Cell metabolism.

[14]  J. Powell,et al.  Targeting T cell metabolism to regulate T cell activation, differentiation and function in disease. , 2017, Current opinion in immunology.

[15]  O. Elemento,et al.  Lymphatic endothelial S1P promotes naïve T cell mitochondrial function and survival , 2017, Nature.

[16]  Russell G. Jones,et al.  MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells. , 2017, Immunity.

[17]  J. Powell,et al.  mTORC1 Promotes T-bet Phosphorylation To Regulate Th1 Differentiation , 2017, The Journal of Immunology.

[18]  Michael D. Buck,et al.  Metabolic Instruction of Immunity , 2017, Cell.

[19]  L. O’Neill,et al.  Mitochondria are the powerhouses of immunity , 2017, Nature Immunology.

[20]  Erin C O'Connor,et al.  Reactive oxygen species are required for driving efficient and sustained aerobic glycolysis during CD4+ T cell activation , 2017, PloS one.

[21]  T. Mak,et al.  Glutathione Primes T Cell Metabolism for Inflammation , 2017, Immunity.

[22]  J. Asara,et al.  Inhibiting Oxidative Phosphorylation In Vivo Restrains Th17 Effector Responses and Ameliorates Murine Colitis , 2017, The Journal of Immunology.

[23]  J. Wolchok,et al.  Cancer immunotherapy — immune checkpoint blockade and associated endocrinopathies , 2017, Nature Reviews Endocrinology.

[24]  Anping Li,et al.  Chimeric antigen receptor T cells: a novel therapy for solid tumors , 2017, Journal of Hematology & Oncology.

[25]  Haiyan Tan,et al.  Integrative Proteomics and Phosphoproteomics Profiling Reveals Dynamic Signaling Networks and Bioenergetics Pathways Underlying T Cell Activation , 2017, Immunity.

[26]  P. Puigserver,et al.  Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism , 2017, Nature.

[27]  David M. Sabatini,et al.  mTOR Signaling in Growth, Metabolism, and Disease , 2017, Cell.

[28]  D. Sabatini,et al.  mTOR Signaling in Growth, Metabolism, and Disease , 2017, Cell.

[29]  W. Lim,et al.  The Principles of Engineering Immune Cells to Treat Cancer , 2017, Cell.

[30]  Takla Griss,et al.  Serine Is an Essential Metabolite for Effector T Cell Expansion. , 2017, Cell metabolism.

[31]  F. Issa Foxp3 and Toll-Like Receptor Signaling Balance Treg Cell Anabolic Metabolism for Suppression , 2017 .

[32]  J. Olefsky,et al.  Inflammatory mechanisms linking obesity and metabolic disease , 2017, The Journal of clinical investigation.

[33]  M. Demetriou,et al.  Glycolysis and glutaminolysis cooperatively control T cell function by limiting metabolite supply to N-glycosylation , 2016, eLife.

[34]  U. Klein,et al.  Anabolism-Associated Mitochondrial Stasis Driving Lymphocyte Differentiation over Self-Renewal. , 2016, Cell reports.

[35]  K. Yokote,et al.  Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARγ directs early activation of T cells , 2016, Nature Communications.

[36]  A. Goldrath,et al.  Constitutive Glycolytic Metabolism Supports CD8+ T Cell Effector Memory Differentiation during Viral Infection. , 2016, Immunity.

[37]  P. Massion,et al.  Fluorescence-based measurement of cystine uptake through xCT shows requirement for ROS detoxification in activated lymphocytes. , 2016, Journal of immunological methods.

[38]  J. Beltman,et al.  Combination Approaches with Immune-Checkpoint Blockade in Cancer Therapy , 2016, Front. Oncol..

[39]  C. Leslie,et al.  Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism , 2016, Science.

[40]  Scott A. Brown,et al.  mTORC1 and mTORC2 Kinase Signaling and Glucose Metabolism Drive Follicular Helper T Cell Differentiation. , 2016, Immunity.

[41]  Y. Belkaid,et al.  Oxygen Sensing by T Cells Establishes an Immunologically Tolerant Metastatic Niche , 2016, Cell.

[42]  E. Wherry,et al.  Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion. , 2016, Immunity.

[43]  Feeling Worn Out? PGC1α to the Rescue for Dysfunctional Mitochondria in T Cell Exhaustion. , 2016, Immunity.

[44]  G. V. D. van der Windt,et al.  Suppression of Glut1 and Glucose Metabolism by Decreased Akt/mTORC1 Signaling Drives T Cell Impairment in B Cell Leukemia , 2016, The Journal of Immunology.

[45]  W. Ellmeier,et al.  The AMP analog AICAR modulates the Treg/Th17 axis through enhancement of fatty acid oxidation , 2016, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[46]  Yang Feng,et al.  Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. , 2016, The Journal of clinical investigation.

[47]  T. Sparwasser,et al.  Disruption of de novo fatty acid synthesis via acetyl‐CoA carboxylase 1 inhibition prevents acute graft‐versus‐host disease , 2016, European journal of immunology.

[48]  Michal Sheffer,et al.  Mitochondrial Biogenesis and Proteome Remodeling Promote One-Carbon Metabolism for T Cell Activation. , 2016, Cell metabolism.

[49]  O. Kretz,et al.  Mitochondrial Dynamics Controls T Cell Fate through Metabolic Programming , 2016, Cell.

[50]  A. D’Alessandro,et al.  Fine-Tuning of CD8(+) T Cell Mitochondrial Metabolism by the Respiratory Chain Repressor MCJ Dictates Protection to Influenza Virus. , 2016, Immunity.

[51]  E. Ma,et al.  Memory CD8(+) T Cells Require Increased Concentrations of Acetate Induced by Stress for Optimal Function. , 2016, Immunity.

[52]  Nancie J. MacIver,et al.  Leptin directly promotes T‐cell glycolytic metabolism to drive effector T‐cell differentiation in a mouse model of autoimmunity , 2016, European journal of immunology.

[53]  L. Turka,et al.  Immunometabolism of regulatory T cells , 2016, Nature Immunology.

[54]  Jonathan H. Esensten,et al.  CD28 Costimulation: From Mechanism to Therapy. , 2016, Immunity.

[55]  G. Freeman,et al.  Coinhibitory Pathways in Immunotherapy for Cancer. , 2016, Annual review of immunology.

[56]  B. Metzler,et al.  Restricting Glutamine or Glutamine-Dependent Purine and Pyrimidine Syntheses Promotes Human T Cells with High FOXP3 Expression and Regulatory Properties , 2016, The Journal of Immunology.

[57]  Linda V. Sinclair,et al.  Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy , 2016, Nature Immunology.

[58]  E. Wherry,et al.  Combination Cancer Therapies with Immune Checkpoint Blockade: Convergence on Interferon Signaling , 2016, Cell.

[59]  D. Munn,et al.  Immune suppressive mechanisms in the tumor microenvironment. , 2016, Current opinion in immunology.

[60]  Greg M. Delgoffe,et al.  Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8 T cell differentiation , 2016, Nature Immunology.

[61]  D. Green,et al.  Metabolic Maintenance of Cell Asymmetry following Division in Activated T Lymphocytes , 2016, Nature.

[62]  S. Manalis,et al.  Amino Acids Rather than Glucose Account for the Majority of Cell Mass in Proliferating Mammalian Cells. , 2016, Developmental cell.

[63]  J. Locasale,et al.  The Warburg Effect: How Does it Benefit Cancer Cells? , 2016, Trends in biochemical sciences.

[64]  Brian Keith,et al.  Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. , 2016, Immunity.

[65]  F. Carbone,et al.  The Proteomic Landscape of Human Ex Vivo Regulatory and Conventional T Cells Reveals Specific Metabolic Requirements , 2016, Immunity.

[66]  R. Wanders,et al.  The Biochemistry and Physiology of Mitochondrial Fatty Acid β-Oxidation and Its Genetic Disorders. , 2016, Annual review of physiology.

[67]  J. Albeck,et al.  Phosphoinositide 3-Kinase regulates glycolysis through mobilization of Aldolase A from the actin cytoskeleton , 2014, Cancer & Metabolism.

[68]  F. Marincola,et al.  Mitochondrial Membrane Potential Identifies Cells with Enhanced Stemness for Cellular Therapy. , 2016, Cell metabolism.

[69]  S. Tay,et al.  The Immune-Metabolic Basis of Effector Memory CD4+ T Cell Function under Hypoxic Conditions , 2016, The Journal of Immunology.

[70]  D. Green,et al.  Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis , 2015, Nature Immunology.

[71]  S. Varambally,et al.  Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction , 2015, Nature Immunology.

[72]  Khalid W. Kalim,et al.  RhoA orchestrates glycolysis for TH2 cell differentiation and allergic airway inflammation. , 2016, The Journal of allergy and clinical immunology.

[73]  Simon C Watkins,et al.  The Tumor Microenvironment Represses T Cell Mitochondrial Biogenesis to Drive Intratumoral T Cell Metabolic Insufficiency and Dysfunction. , 2016, Immunity.

[74]  V. De Rosa,et al.  Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants , 2015, Nature Immunology.

[75]  Loise M. Francisco,et al.  The PTEN pathway in Tregs is a critical driver of the suppressive tumor microenvironment , 2015, Science Advances.

[76]  John P. Ray,et al.  The Interleukin-2-mTORc1 Kinase Axis Defines the Signaling, Differentiation, and Metabolism of T Helper 1 and Follicular B Helper T Cells. , 2015, Immunity.

[77]  D. Chang,et al.  Glucosamine Modulates T Cell Differentiation through Down-regulating N-Linked Glycosylation of CD25* , 2015, The Journal of Biological Chemistry.

[78]  Philippe A. Robert,et al.  Glutamine-dependent α-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation , 2015, Science Signaling.

[79]  E. Wherry,et al.  Acetyl CoA Carboxylase 2 Is Dispensable for CD8+ T Cell Responses , 2015, PloS one.

[80]  J. Locasale,et al.  Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses , 2015, Cell.

[81]  R. Schreiber,et al.  Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression , 2015, Cell.

[82]  M. Moser,et al.  Cutting Edge: Hypoxia-Inducible Factor 1 Negatively Regulates Th1 Function , 2015, The Journal of Immunology.

[83]  K. Yokote,et al.  Obesity Drives Th17 Cell Differentiation by Inducing the Lipid Metabolic Kinase, ACC1. , 2015, Cell reports.

[84]  N. Chandel Evolution of Mitochondria as Signaling Organelles. , 2015, Cell metabolism.

[85]  Matthew J. Rardin,et al.  SIRT5 Regulates both Cytosolic and Mitochondrial Protein Malonylation with Glycolysis as a Major Target. , 2015, Molecular cell.

[86]  I. Coe,et al.  N-linked glycosylation of human SLC1A5 (ASCT2) transporter is critical for trafficking to membrane. , 2015, Biochimica et biophysica acta.

[87]  M. Abdellatif,et al.  Mitochondrial complex II is a source of the reserve respiratory capacity that is regulated by metabolic sensors and promotes cell survival , 2015, Cell Death and Disease.

[88]  Ana I. Domingos,et al.  Leptin Receptor Signaling in T Cells Is Required for Th17 Differentiation , 2015, The Journal of Immunology.

[89]  Burkhard Becher,et al.  Immune attack: the role of inflammation in Alzheimer disease , 2015, Nature Reviews Neuroscience.

[90]  Robert A. Amezquita,et al.  IL-7-Induced Glycerol Transport and TAG Synthesis Promotes Memory CD8+ T Cell Longevity , 2015, Cell.

[91]  Greg M. Delgoffe,et al.  mTORC1 and mTORC2 selectively regulate CD8⁺ T cell differentiation. , 2015, The Journal of clinical investigation.

[92]  B. Malissen,et al.  Early T cell activation: integrating biochemical, structural, and biophysical cues. , 2015, Annual review of immunology.

[93]  Christine M. Miller,et al.  Antigen- and cytokine-driven accumulation of regulatory T cells in visceral adipose tissue of lean mice. , 2015, Cell metabolism.

[94]  G. Freeman,et al.  PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation , 2015, Nature Communications.

[95]  B. Tu,et al.  Acetyl-CoA and the Regulation of Metabolism: Mechanisms and Consequences , 2015, Current opinion in cell biology.

[96]  S. A. van de Pavert,et al.  Identification of natural RORγ ligands that regulate the development of lymphoid cells. , 2015, Cell metabolism.

[97]  Erika L. Pearce,et al.  Targeting T cell metabolism for therapy. , 2015, Trends in immunology.

[98]  T. Sparwasser,et al.  Fatty acid metabolism in the regulation of T cell function. , 2015, Trends in immunology.

[99]  P. Toogood,et al.  Sterol metabolism controls T(H)17 differentiation by generating endogenous RORγ agonists. , 2015, Nature chemical biology.

[100]  E. E. Vincent,et al.  The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. , 2015, Immunity.

[101]  Mark S. Sundrud,et al.  Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. , 2015, Cancer research.

[102]  S. Crotty T follicular helper cell differentiation, function, and roles in disease. , 2014, Immunity.

[103]  Nataliya Gorinski,et al.  De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells , 2014, Nature Medicine.

[104]  Sarah L. Gaffen,et al.  The IL-23–IL-17 immune axis: from mechanisms to therapeutic testing , 2014, Nature Reviews Immunology.

[105]  K. Oestreich,et al.  Bcl-6 directly represses the gene program of the glycolysis pathway , 2014, Nature Immunology.

[106]  M. Birnbaum,et al.  Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. , 2014, Immunity.

[107]  J. Rathmell,et al.  The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. , 2014, Cell metabolism.

[108]  M. David,et al.  Unconventional post-translational modifications in immunological signaling , 2014, Nature Immunology.

[109]  N. Chandel,et al.  ROS Function in Redox Signaling and Oxidative Stress , 2014, Current Biology.

[110]  M. Horton,et al.  The AGC kinase SGK1 regulates TH1 and TH2 differentiation downstream of the mTORC2 complex , 2014, Nature Immunology.

[111]  E. Wherry,et al.  Regulator of Fatty Acid Metabolism, Acetyl Coenzyme A Carboxylase 1, Controls T Cell Immunity , 2014, The Journal of Immunology.

[112]  Dean Sheppard,et al.  TGF-β activation and function in immunity. , 2014, Annual review of immunology.

[113]  J. Rathmell,et al.  Leptin Metabolically Licenses T Cells for Activation To Link Nutrition and Immunity , 2014, The Journal of Immunology.

[114]  Kassem M. Makki,et al.  Adipose Tissue in Obesity-Related Inflammation and Insulin Resistance: Cells, Cytokines, and Chemokines , 2013, ISRN inflammation.

[115]  D. Guertin,et al.  T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. , 2013, Immunity.

[116]  J. Linden,et al.  Extracellular adenosine regulates naive T cell development and peripheral maintenance , 2013, The Journal of experimental medicine.

[117]  E. Yang,et al.  Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen , 2013, Nature Immunology.

[118]  David A. Forero-Peña,et al.  Statins as Modulators of Regulatory T-Cell Biology , 2013, Mediators of inflammation.

[119]  C. Hess,et al.  Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch , 2013, Nature Immunology.

[120]  P. Muranski,et al.  Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. , 2013, The Journal of clinical investigation.

[121]  Sara Cipolat,et al.  Mitochondrial Cristae Shape Determines Respiratory Chain Supercomplexes Assembly and Respiratory Efficiency , 2013, Cell.

[122]  B. Faubert,et al.  CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability , 2013, Proceedings of the National Academy of Sciences.

[123]  B. Cravatt,et al.  Functional Lysine Modification by an Intrinsically Reactive Primary Glycolytic Metabolite , 2013, Science.

[124]  J. Dennis,et al.  Probing the hexosamine biosynthetic pathway in human tumor cells by multitargeted tandem mass spectrometry. , 2013, ACS chemical biology.

[125]  B. Faubert,et al.  Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis , 2013, Cell.

[126]  D. Mathis Immunological goings-on in visceral adipose tissue. , 2013, Cell metabolism.

[127]  Linda V. Sinclair,et al.  Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation , 2013, Nature Immunology.

[128]  R. Zamoyska,et al.  T cell receptor signalling networks: branched, diversified and bounded , 2013, Nature Reviews Immunology.

[129]  J. Rathmell,et al.  Metabolic regulation of T lymphocytes. , 2013, Annual review of immunology.

[130]  J. Licht,et al.  Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. , 2013, Immunity.

[131]  David K. Finlay,et al.  AMPKα1: A glucose sensor that controls CD8 T-cell memory , 2013, European journal of immunology.

[132]  C. Benoist,et al.  PPARγ is a major driver of the accumulation and phenotype of adipose-tissue Treg cells , 2012, Nature.

[133]  M. Horton,et al.  Regulation of immune responses by mTOR. , 2012, Annual review of immunology.

[134]  J. Sprent,et al.  The role of interleukin-2 during homeostasis and activation of the immune system , 2012, Nature Reviews Immunology.

[135]  G. V. D. van der Windt,et al.  Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. , 2012, Immunity.

[136]  D. Green,et al.  The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. , 2011, Immunity.

[137]  Takla Griss,et al.  The Liver Kinase B1 Is a Central Regulator of T Cell Development, Activation, and Metabolism , 2011, The Journal of Immunology.

[138]  Yi Zhang,et al.  The First Identification of Lysine Malonylation Substrates and Its Regulatory Enzyme* , 2011, Molecular & Cellular Proteomics.

[139]  F. Marincola,et al.  A human memory T-cell subset with stem cell-like properties , 2011, Nature Medicine.

[140]  Jin Ye,et al.  Regulation of cholesterol and fatty acid synthesis. , 2011, Cold Spring Harbor perspectives in biology.

[141]  P. Worley,et al.  The mammalian Target of Rapamycin (mTOR) regulates T helper cell differentiation through the selective activation of mTORC1 and mTORC2 signaling , 2011, Nature Immunology.

[142]  J. Rathmell,et al.  Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs Are Essential for Effector and Regulatory CD4+ T Cell Subsets , 2011, The Journal of Immunology.

[143]  L. Scorrano,et al.  During autophagy mitochondria elongate, are spared from degradation and sustain cell viability , 2011, Nature Cell Biology.

[144]  B. Viollet,et al.  Phosphorylation of ULK1 (hATG1) by AMP-Activated Protein Kinase Connects Energy Sensing to Mitophagy , 2011, Science.

[145]  Zhihong Zhang,et al.  Identification of lysine succinylation as a new post-translational modification. , 2011, Nature chemical biology.

[146]  E. Negelein,et al.  THE METABOLISM OF CARCINOMA CELLS , 2011 .

[147]  M. Hentze,et al.  The REM phase of gene regulation. , 2010, Trends in biochemical sciences.

[148]  K. Frauwirth,et al.  Glutamine Uptake and Metabolism Are Coordinately Regulated by ERK/MAPK during T Lymphocyte Activation , 2010, The Journal of Immunology.

[149]  浦田 将久 Role of hypoxia-inducible factor 1α in T cells as a negative regulator in development of vascular remodeling , 2010 .

[150]  Russell G. Jones,et al.  Enhancing CD8 T-cell memory by modulating fatty acid metabolism , 2009, Nature.

[151]  P. Worley,et al.  The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. , 2009, Immunity.

[152]  L. Cantley,et al.  Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation , 2009, Science.

[153]  R. Ahmed,et al.  mTOR regulates memory CD8 T cell differentiation , 2009, Nature.

[154]  Paula D. Bos,et al.  Metastasis: from dissemination to organ-specific colonization , 2009, Nature Reviews Cancer.

[155]  Greg M. Delgoffe,et al.  Anergic T Cells Are Metabolically Anergic , 2009 .

[156]  A. Khoruts,et al.  De novo induction of antigen‐specific CD4+CD25+Foxp3+ regulatory T cells in vivo following systemic antigen administration accompanied by blockade of mTOR , 2008, Journal of leukocyte biology.

[157]  J. Rathmell,et al.  Glucose Uptake Is Limiting in T Cell Activation and Requires CD28-Mediated Akt-Dependent and Independent Pathways1 , 2008, The Journal of Immunology.

[158]  B. Viollet,et al.  AMP‐activated protein kinase regulates lymphocyte responses to metabolic stress but is largely dispensable for immune cell development and function , 2008, European journal of immunology.

[159]  A. Keating,et al.  Functional properties and genomics of glucose transporters. , 2007, Current genomics.

[160]  John T. Chang,et al.  Asymmetric T Lymphocyte Division in the Initiation of Adaptive Immune Responses , 2007, Science.

[161]  V. De Rosa,et al.  A key role of leptin in the control of regulatory T cell proliferation. , 2007, Immunity.

[162]  Michael D. Schneider,et al.  A pivotal role for endogenous TGF-β-activated kinase-1 in the LKB1/AMP-activated protein kinase energy-sensor pathway , 2006, Proceedings of the National Academy of Sciences.

[163]  D. Valmori,et al.  Rapamycin-Mediated Enrichment of T Cells with Regulatory Activity in Stimulated CD4+ T Cell Cultures Is Not Due to the Selective Expansion of Naturally Occurring Regulatory T Cells but to the Induction of Regulatory Functions in Conventional CD4+ T Cells1 , 2006, The Journal of Immunology.

[164]  R. D'Hooge,et al.  Mitochondrial Rhomboid PARL Regulates Cytochrome c Release during Apoptosis via OPA1-Dependent Cristae Remodeling , 2006, Cell.

[165]  D. Hardie,et al.  Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes , 2006, The Journal of experimental medicine.

[166]  C. Mantzoros,et al.  Leptin Receptor Expression and Signaling in Lymphocytes: Kinetics During Lymphocyte Activation, Role in Lymphocyte Survival, and Response to High Fat Diet in Mice1 , 2006, The Journal of Immunology.

[167]  H. Weiner,et al.  Immunology and immunotherapy of Alzheimer's disease , 2006, Nature Reviews Immunology.

[168]  Craig B. Thompson,et al.  Fuel feeds function: energy metabolism and the T-cell response , 2005, Nature Reviews Immunology.

[169]  M. Battaglia,et al.  Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. , 2005, Blood.

[170]  R. Loewith,et al.  Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive , 2004, Nature Cell Biology.

[171]  Nathan Laniewski,et al.  Antioxidant Treatment Reduces Expansion and Contraction of Antigen-Specific CD8+ T Cells during Primary but Not Secondary Viral Infection , 2004, Journal of Virology.

[172]  J. Kwon,et al.  T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation , 2004, Nature Immunology.

[173]  N. Ruderman,et al.  Malonyl-CoA and AMP-activated protein kinase: An expanding partnership , 2003, Molecular and Cellular Biochemistry.

[174]  C. Thompson,et al.  The CD28 signaling pathway regulates glucose metabolism. , 2002, Immunity.

[175]  M. Debenedette,et al.  4-1BB Ligand Induces Cell Division, Sustains Survival, and Enhances Effector Function of CD4 and CD8 T Cells with Similar Efficacy1 , 2001, The Journal of Immunology.

[176]  Y. Yazaki,et al.  The role of N‐glycosylation in the targeting and stability of GLUT1 glucose transporter , 1993, FEBS letters.