Interplay Between Metabolic Sensors and Immune Cell Signaling

  • Prashant Chauhan
  • Arup Sarkar
  • Bhaskar Saha
Part of the Experientia Supplementum book series (EXS, volume 109)


The immune system, like all other systems, responds to perturbations of the baseline, homeostatic functioning of immune cells. These perturbations come in the form of infection, tumors, autoantigens, and can occur after mismatched transplantation. During response, immune cells alter their metabolic activities. However, the subsets of the same cell type differ to distinctively associate specific immune function to a particular metabolic profile. The response is mounted as a joint function of metabolic receptor and immune receptor signaling that target various metabolic pathways: glycolysis the pentose phosphate pathway; oxidative phosphorylation; beta-oxidation of fatty acids and transamination. The products from these cycles are integrated in the tricarboxylic acid cycle. However, many more pathways lead to many secondary metabolites that are not directly related to energy derivation or maintaining structure of the cells. These secondary metabolites can again work in an autocrine manner to re-tune the immune cells to optimize their restorative effector functions.


Leishmania Macrophage metabolism Immunometabolomic Neutrophil metabolism Lymphocyte metabolism Metabolic regulation of immune response 



The work has been recommended by Infect-ERA (Project INLEISH) and was funded by the Department of Biotechnology, New Delhi, Government of India. The grant number is BT/IN/Infect-ERA/33/BS/2016-17.



T cells anergy is a tolerance mechanism by which lymphocytes become intrinsically refractory to antigenic sensitization, but do not undergo apoptosis readily. Instead, they exhibit loss in functionality and a state of hyporesponsiveness in their effector functions. Anergy affects both CD4+ and CD8+ lymphocytes, and two major mechanisms underlying this obscure phenomenon are documented: (1) Clonal anergy, which is predominantly characterized as growth arrest. This type of anergy arises from incomplete T cell activation and is observed in T cells which have undergone prior activation. Mechanistically, blockade in the Ras/MAPK pathway might be responsible for such observed numbness, and, evidently, it has been suggested that IL-2 or anti-OX40 signaling could reverse such a phenotype. (2) Adaptive tolerance, which represents a more generalized inhibition of proliferation and effector functions. This type of anergy is initiated in naïve T cell in vivo by an inadequate environmental stimulus of deficit costimulatory signals provided by CD28 or dominant inhibitory signals from coinhibitory molecules such as PD-1 and PD-L1 or even both. It has been shown that blockade of the interaction between PD-1 and its ligands PD-L1 and PD-L2 prevents anergy induction in iNKT cells. Adaptive tolerance can be induced in the thymus as well as in peripheral lymphoid organs. When persistent antigen is encountered, T cells block receptor tyrosine kinase activity, which ablates calcium mobilization, and also another independent mechanism involving the IL-2 signaling cascade.

First responders

In the metazoan body, the immune system carries out specialized functions that coordinate several responses when encounters with a foreign microorganism/their derivatives take place. A myriad of such responses includes the induction of an inflammatory environment and coordinated execution of genes responsible for the activation and mobilization of cells of the immune system. Such highly tailored responses to external stimulus are mediated by, neutrophils, dendritic cells, macrophages, T cells, and B cells, along with other immune cells. These immune cells experiences dramatic shifts in their metabolic profiles upon activation, making them adequate to combat the infection directly (by synthesizing antimicrobial peptides, nitric oxide, and ROS) and indirectly (pleiotropic factors such as chemokines and cytokines, which attract and activate cells of the adaptive immune system), and, thus, making them first responders to any exogenous pathogenic stimulus.


The cellular economy is monetized by adenosine triphosphate (ATP). ATP is generated in a cell by two major pathways, glycolysis and oxidative phosphorylation. Depending upon the requirement of a cell, metabolism can shift towards the anabolic module (the de novo or salvage construction of molecules required for growth and biomass production) or the catabolic module (the breakdown of macromolecules into yet smaller molecules for the production of energy). The glycolytic pathway converts glucose into pyruvate via a series of intermediate metabolites that can enter other pathways (such as the pentose phosphate pathway PPP) and contribute to biosynthesis and cell growth. Glycolysis also leads to the conversion of two molecules of coenzyme NAD+ to NADH, and the overall process can be summarized as:Glucose + 2NAD +  + 2ADP + 2P i  ➔ Pyruvate + 2NADH + 2ATP + 2H +  + 2H 2 O

Histone deacetylases

Histone tails are positively charged, owing to amine groups present on their lysine and arginine AA residues. These positive charges help the histone tails to interact with and bind to the negatively charged phosphate groups on the DNA backbone. HDACs are a class of enzymes that remove acetyl groups (O=C–CH3) from an ε-N-acetyl lysine amino acid on a histone, allowing the histones to wrap the DNA more tightly. This decreased binding allows chromatin expansion, permitting genetic transcription to take place.

Insulin resistance

Insulin is secreted by β cells in the pancreas contained within islets clusters. Insulin is synthesized and secreted by these cells. The blood sugar level spikes after meals; in response, this provides a neuroendocrine stimulus to the pancreas (by the hypothalamus) to secrete insulin into the blood. There, insulin helps muscle, fat, and the liver absorb glucose from the bloodstream, lowering blood glucose levels. Insulin stimulates hepatocytes and muscle cells to store excess glucose in a process known as gluconeogenesis. Insulin also provides a positive feedback to hepatocytes to reduce glucose production in order to maintain glucose homeostasis in the body. In case of insulin resistance, muscle, adipose cells, and hepatocytes do not respond optimally to insulin and, thus, fail to absorb glucose from the bloodstream. The reasons for insulin resistance can be numerous, such as high fat intake causes obesity and obesity-induced inflammation, in case of cardiovascular diseases, insufficient physical exercise, excess FA-induced mitochondrial dysfunction, and many other factors, such as lifestyle, etc. As a consequence of this, β cells in the pancreas try to meet the elevated demand for insulin by producing more insulin but, consequentially over time, insulin resistance can lead to type 2 diabetes because, ultimately, β cells fail to supply enough insulin to the body. As a result, blood glucose levels build up, leading to serious metabolic syndromes.

Metabolic reprogramming

As the concept of metabolic regulation of the immune system gained wider acceptance over years, the importance of bidirectional regulation of the immune system and their effector functions dictated by their metabolic status became clearer. Activated T cells significantly upregulate glucose, amino acid, and iron uptakes, compensating the requirements for active biosynthesis of nascent proteins, DNA, and lipids that are linked to proliferation and growth. To undergo a polarization under signals like cytokines, inflammatory mediators, or direct physical engagement via PAMP-TLR or the MHC–Peptide–TCR complex with pathogenic moieties, it is mandatory for immune cells to rewire their metabolic network. These dramatic metabolic transitions in T cells that are crucial for supporting their activation and function are termed as ‘metabolic reprogramming’. The effects of immune cells include cytokine activation of cells such as adipocytes and hepatocytes, which are the central hub of mediating systemic metabolic changes (for example, in metabolic disorders such as type 2 diabetes and obesity-induced inflammation). In addition, the concept of reciprocal regulation of immune cells by host-commensal microbiota-derived metabolites and nutritive status of the body influencing the immune cells is now very well documented. Such multifaceted chemical interactions between different cells of the body with lymphocytes and macrophages eventually shape the immune responses significantly.

Oxidative phosphorylation

Glycolysis and the TCA cycle help maintain the NAD+–NADH redox balance in a cell and the NADH and FADH2 molecules are used to donate electrons to the electron transport chain on the inner membrane of a mitochondrion for oxidative phosphorylation. For each molecule of FADH2 or NADH oxidized, two or three molecules of ATP, respectively, are generated. Redox reactions in the oxidative phosphorylation sequentially transfer electrons to generate a proton (H+) gradient across the inner membrane of mitochondria, which drives the synthesis of ATP. Although immune cells utilize other metabolic pathways such as the pentose phosphate pathway, glutaminolysis, and fatty acid oxidation, the common molecule integrating these pathways is glucose.

Pentose phosphate pathway

Generates ribose for nucleotide synthesis. During this process, NADH+ is reduced to NADPH, forming the cofactor for ROS generation via the NADPH oxidase (NPhox) system in phagocytic cells.

Primary metabolites

A primary metabolite is a kind of metabolite that is directly involved in normal growth, development, and reproduction. It usually performs a physiological function in the organism (i.e., an intrinsic function). A primary metabolite is typically present in many organisms or cells. Major examples include amino acids (AA), alcohols, vitamins, polyols, organic acids, and nucleotides. Metabolites from external sources such as products from microbial growth are also primary metabolites.

TCA cycle

Acetyl-CoA can also undergo alternate fates, i.e., its conversion to lactate, which is excreted from cells. Acetyl-CoA (2C) enters the TCA cycle to combine with oxaloacetic acid (4C) and yield citrate (6C). Through a sequential set of reactions, citrate is completely oxidized to CO2 and oxaloacetic acid is regenerated. The TCA cycle completes the oxidation of glucose to six molecules of CO2, generating two molecules of GTP (guanosine triphosphate), ten molecules of NADH, and two molecules of reduced FAD (FADH2). The TCA cycle provides intermediates that can be exported to cytosol for fatty acid synthesis. The NADH thus formed as a product in the above step needs to be recycled. In anaerobic organisms or hypoxic mammalian cells, NAD+ is regenerated from NADH by the conversion of pyruvate to lactate. In aerobic organisms, the NADH and pyruvate that are generated by glycolysis are transported to mitochondria. One carbon of each pyruvate molecule is released as carbon dioxide (CO2) and one molecule of NADH is generated; the remaining two carbons are added to a carrier, coenzyme A, to yield acetyl-CoA, which acts as a connecting link between glycolysis and the TCA cycle.


A chemical reaction that transfers an amino group to a ketoacid to form new amino acids. This pathway is responsible for the deamination of most amino acids. During glutaminolysis, α-ketoglutarate is generated from glutamine. Glutamine thus plays dual functions: replenishing the exhausted intermediates of the TCA cycle and complete oxidation to generate ATP. The choice that immune cells make to divert glutaminolysis in either direction depends on the energy requirements during states like infection and homeostasis. The β-oxidation of fatty acids also yields acetyl-CoA, which is burnt through the TCA cycle.

Warburg effect

Under oxygen-plentiful conditions, non-proliferative tissues preferentially metabolize glucose to pyruvate via glycolysis, and then completely oxidize most of the pyruvate in the mitochondria to CO2 and generate energy via a process known as oxidative phosphorylation (OxPhos). Because the oxygen is required as the final electron acceptor to completely oxidize glucose, this process is obligatorily aerobic. Thus, when hypoxic conditions are encountered, cells divert the pyruvate generated via glycolysis away from OxPhos by generating lactose. Lactate production allows glycolysis to continue (since NADH cycles back to NAD+), but limits ATP production in comparison to OxPhos. Sir Otto Warburg made a pioneering discovery that cancer cells are inherently skewed towards converting most glucose to lactate in spite of utopic oxygenation. This aerobic glycolysis is also reported to occur in normal proliferative cells besides transformed malignant cells. While this mode of generating energy is far less efficient as compared to OxPhos, it justifies the explanation for faster glucose utilization rates exhibited by cancerous cells. Another plausible explanation for enhanced conversion of glucose to lactate by tumor cells is that HIF-1α is stabilized and accumulates in cytosol upon hypoxic induction. HIF-1α transactivates the glycolytic genes, as well as activating the PDK1 gene, which is responsible for the conversion of pyruvate to acetyl-CoA. Acetyl-CoA enters the TCA cycle, which donates electrons to mitochondrial respiratory chain complexes I to IV. Increased activity of transcription factors such as myc and HIF-1α coordinates with the loss of tumor suppressive function of p53. A loss of function of p53 correlates with the increase of Glut transporters (transcription and surface translocation) via NF-κB. In addition, mitochondrial biogenesis promoted by myc results in the overproduction of ROS. ROS can cause mtDNA spontaneous mutations, rendering mitochondrial enzymes dysfunctional and, thus, OxPhos, leaving only aerobic glycolysis, a probable mode of energy production in transformed cells.


  1. Akira S, Uematsu S, Takeuchi O (2006) Pathogen recognition and innate immunity. Cell 124:783–801PubMedCrossRefGoogle Scholar
  2. Alba-Loureiro TC, Munhoz CD, Martins JO, Cerchiaro GA, Scavone C, Curi R, Sannomiya P (2007) Neutrophil function and metabolism in individuals with diabetes mellitus. Braz J Med Biol Res 40:1037–1044PubMedCrossRefGoogle Scholar
  3. Albert D, Kowalski J, Nodzenski E, Micek M, Wu P (1990) The dose dependent effect of cyclic AMP on ribonucleotide reductase in mitogen stimulated mononuclear cells. Biochem Biophys Res Commun 167:383–390PubMedCrossRefGoogle Scholar
  4. Alers S, Löffler AS, Wesselborg S, Stork B (2012) Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol 32:2–11PubMedPubMedCentralCrossRefGoogle Scholar
  5. Alonso D, Nungester WJ (1956) Comparative study of host resistance of guinea pigs and rats: V. The effect of pneumococcal products on glycolysis and oxygen uptake by polymorphonuclear leucocytes. J Infect Dis 99:174–181PubMedCrossRefGoogle Scholar
  6. Amiel E, Everts B, Fritz D, Beauchamp S, Ge B, Pearce EL, Pearce EJ (2014) Mechanistic target of rapamycin inhibition extends cellular lifespan in dendritic cells by preserving mitochondrial function. J Immunol 193:2821–2830PubMedPubMedCentralCrossRefGoogle Scholar
  7. Amkraut A, Solomon GF (1974) From the symbolic stimulus to the pathophysiologic response: Immune mechanisms. Int J Psych Med 5:541–563CrossRefGoogle Scholar
  8. Amulic B, Cazalet C, Hayes GL, Metzler KD, Zychlinsky A (2012) Neutrophil function: from mechanisms to disease. Annu Rev Immunol 30:459–489PubMedCrossRefGoogle Scholar
  9. Ananieva EA, Patel CH, Drake CH, Powell JD, Hutson SM (2014) Cytosolic branched chain aminotransferase (BCATc) regulates mTORC1 signaling and glycolytic metabolism in CD4+ T cells. J Biol Chem 289:18793–18804PubMedPubMedCentralCrossRefGoogle Scholar
  10. Araki K, Turner AP, Shaffer VO, Gangappa S, Keller SA, Bachmann MF, Larsen CP, Ahmed R (2009) mTOR regulates memory CD8 T-cell differentiation. Nature 460:108–112PubMedPubMedCentralCrossRefGoogle Scholar
  11. Arany Z, Huang LE, Eckner R, Bhattacharya S, Jiang C, Goldberg MA, Bunn HF, Livingston DM (1996) An essential role for p300/CBP in the cellular response to hypoxia. Proc Natl Acad Sci USA 93:12969–12973PubMedPubMedCentralCrossRefGoogle Scholar
  12. Averous J, Fonseca BD, Proud CG (2008) Regulation of cyclin D1 expression by mTORC1 signaling requires eukaryotic initiation factor 4E-binding protein 1. Oncogene 27:1106–1113PubMedCrossRefGoogle Scholar
  13. Avruch J, Long X, Lin Y, Ortiz-Vega S, Rapley J, Papageorgiou A, Oshiro N, Kikkawa U (2009) Activation of mTORC1 in two steps: rheb-GTP activation of catalytic function and increased binding of substrates to raptor1. Biochem Soc Trans 37:223–226PubMedCrossRefGoogle Scholar
  14. Balmer ML, Ma EH, Bantug GR, Grählert J, Pfister S, Glatter T, Jauch A, Dimeloe S, Slack E, Dehio P, Krzyzaniak MA (2016) Memory CD8+ T cells require increased concentrations of acetate induced by stress for optimal function. Immunity 44:1312–1324PubMedCrossRefGoogle Scholar
  15. Balsamo M, Manzini C, Pietra G, Raggi F, Blengio F, Mingari MC, Varesio L, Moretta L, Bosco MC, Vitale M (2013) Hypoxia downregulates the expression of activating receptors involved in NK-cell-mediated target cell killing without affecting ADCC. Eur J Immunol 43:2756–2764PubMedCrossRefGoogle Scholar
  16. Bantug GR, Hess C (2016) Glycolysis and EZH2 boost T cell weaponry against tumors. Nat Immunol 17:41–42PubMedCrossRefGoogle Scholar
  17. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, Freeman GJ, Ahmed R (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–687PubMedCrossRefGoogle Scholar
  18. Barragan M, Good M, Kolls JK (2015) Regulation of dendritic cell function by vitamin D. Nutrients 7:8127–8151PubMedPubMedCentralCrossRefGoogle Scholar
  19. Battaglia M, Stabilini A, Roncarolo MG (2005) Rapamycin selectively expands CD4+ CD25+ FoxP3+ regulatory T cells. Blood 105:4743–4748PubMedCrossRefGoogle Scholar
  20. B’chir W, Chaveroux C, Carraro V, Averous J, Maurin AC, Jousse C, Muranishi Y, Parry L, Fafournoux P, Bruhat A (2014) Dual role for CHOP in the crosstalk between autophagy and apoptosis to determine cell fate in response to amino acid deprivation. Cell Signal 26:1385–1391PubMedCrossRefGoogle Scholar
  21. Beier UH, Wang L, Bhatti TR, Liu Y, Han R, Ge G, Hancock WW (2011) Sirtuin-1 targeting promotes Foxp3+ T-regulatory cell function and prolongs allograft survival. Mol Cell Biol 31:1022–1029PubMedPubMedCentralCrossRefGoogle Scholar
  22. Beisel WR (1975) Metabolic response to infection. Annu Rev Med 26:9–20PubMedCrossRefGoogle Scholar
  23. Belkaid Y, Hand TW (2014) Role of the microbiota in immunity and inflammation. Cell 157:121–141PubMedPubMedCentralCrossRefGoogle Scholar
  24. Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE, Attanasio J, Stelekati E, McLane LM, Paley MA, Delgoffe GM, Wherry EJ (2016) Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion. Immunity 45:358–373PubMedPubMedCentralCrossRefGoogle Scholar
  25. Ben-Shoshan J, Maysel-Auslender S, Mor A, Keren G, George J (2008) Hypoxia controls CD4+CD25+ regulatory T-cell homeostasis via hypoxia-inducible factor-1α. Eur J Immunol 38:2412–2418PubMedCrossRefGoogle Scholar
  26. Bensinger SJ, Bradley MN, Joseph SB, Zelcer N, Janssen EM, Hausner MA, Shih R, Parks JS, Edwards PA, Jamieson BD, Tontonoz P (2008) LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134:97–111PubMedPubMedCentralCrossRefGoogle Scholar
  27. Ben-Zvi I, Aranow C, Mackay M, Stanevsky A, Kamen DL, Marinescu LM, Collins CE, Gilkeson GS, Diamond B, Hardin JA (2010) The impact of vitamin D on dendritic cell function in patients with systemic lupus erythematosus. PLoS One 5:e9193PubMedPubMedCentralCrossRefGoogle Scholar
  28. Berger J, Moller DE (2002) The mechanisms of action of PPARs. Annu Rev Med 53:409–435PubMedCrossRefGoogle Scholar
  29. Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S, Harmrolfs K, Sandouk A, Hesse C, Castro CN, Bähre H, Tschirner SK (2014) De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med 20:1327–1333PubMedCrossRefGoogle Scholar
  30. Bhatt AP, Jacobs SR, Freemerman AJ, Makowski L, Rathmell JC, Dittmer DP, Damania B (2012) Dysregulation of fatty acid synthesis and glycolysis in non-Hodgkin lymphoma. Proc Natl Acad Sci USA 109:11818–11823PubMedPubMedCentralCrossRefGoogle Scholar
  31. Biswas SK (2015) Metabolic reprogramming of immune cells in cancer progression. Immunity 43:435–449PubMedCrossRefGoogle Scholar
  32. Blackburn SD, Shin H, Haining WN, Zou T, Workman CJ, Polley A, Betts MR, Freeman GJ, Vignali DA, Wherry EJ (2009) Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 10:29–37PubMedCrossRefGoogle Scholar
  33. Blagih J, Coulombe F, Vincent EE, Dupuy F, Galicia-Vázquez G, Yurchenko E, Raissi TC, van der Windt GJW, Viollet B, Pearce EL, Pelletier J, Piccirillo CA, Krawczyk CM, Divangahi M, Jones RG (2015) The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity. 42:41–54PubMedCrossRefGoogle Scholar
  34. Blouin CC, Pagé EL, Soucy GM, Richard DE (2004) Hypoxic gene activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor 1α. Blood 103:1124–1130PubMedCrossRefGoogle Scholar
  35. Bolster DR, Crozier SJ, Kimball SR, Jefferson LS (2002) AMP-activated protein kinase suppresses protein synthesis in rat skeletal muscle through down-regulated mammalian target of rapamycin (mTOR) signaling. J Biol Chem 277:23977–23980PubMedCrossRefGoogle Scholar
  36. Bonfils G, Jaquenoud M, Bontron S, Ostrowicz C, Ungermann C, De Virgilio C (2012) Leucyl-tRNA synthetase controls TORC1 via the EGO complex. Mol Cell 46:105–110PubMedCrossRefGoogle Scholar
  37. Brach MA, Gruss HJ, Herrmann F (1992) Prolongation of survival of human polymorphonuclear neutrophils by granulocyte-macrophage colony-stimulating factor is caused by inhibition of programmed cell death. Blood 80:2920–2924PubMedGoogle Scholar
  38. Brinkmann V, Reichard U, Goosmann C, Fauler B, Uhlemann Y, Weiss DS, Weinrauch Y, Zychlinsky A (2004) Neutrophil extracellular traps kill bacteria. Science 303:1532–1535PubMedCrossRefGoogle Scholar
  39. Bronietzki AW, Schuster M, Schmitz I (2015) Autophagy in T-cell development, activation and differentiation. Immunol Cell Biol 93:25–34PubMedCrossRefGoogle Scholar
  40. Brown EJ, Albers MW, Shin TB, Ichikawa K, Keith CT, Lane WS, Schreiber SL (1994) A mammalian protein targeted by G1-arresting rapamycin–receptor complex. Nature 369:756PubMedCrossRefGoogle Scholar
  41. Brubaker SW, Bonham KS, Zanoni I, Kagan JC (2015) Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol 33:257–290PubMedPubMedCentralCrossRefGoogle Scholar
  42. Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, Kaelin WG (2004) Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 18:2893–2904PubMedPubMedCentralCrossRefGoogle Scholar
  43. Brunet A, Datta SR, Greenberg ME (2001) Transcription-dependent and-independent control of neuronal survival by the PI3K–Akt signaling pathway. Curr Opin Neurobiol 11:297–305PubMedCrossRefGoogle Scholar
  44. Buck MD, O’Sullivan D, Pearce EL (2015) T cell metabolism drives immunity. J Exp Med 212:1345–1360PubMedPubMedCentralCrossRefGoogle Scholar
  45. Buckley AF, Kuo CT, Leiden JM (2001) Transcription factor LKLF is sufficient to program T cell quiescence via a c-Myc-dependent pathway. Nat Immunol 2:698–704PubMedCrossRefGoogle Scholar
  46. Buescher JM, Antoniewicz MR, Boros LG, Burgess SC, Brunengraber H, Clish CB, DeBerardinis RJ, Feron O, Frezza C, Ghesquiere B, Gottlieb E (2015) A roadmap for interpreting 13C metabolite labeling patterns from cells. Curr Opin Biotechnol 34:189–201PubMedPubMedCentralCrossRefGoogle Scholar
  47. Byersdorfer CA, Tkachev V, Opipari AW, Goodell S, Swanson J, Sandquist S, Glick GD, Ferrara JL (2013) Effector T cells require fatty acid metabolism during murine graft-versus-host disease. Blood 122:3230–3237PubMedPubMedCentralCrossRefGoogle Scholar
  48. Byrne CS, Chambers ES, Morrison DJ, Frost G (2015) The role of short chain fatty acids in appetite regulation and energy homeostasis. Int J Obesity 39:1331–1338CrossRefGoogle Scholar
  49. Cai Q, Lin T, Kamarajugadda S, Lu J (2013) Regulation of glycolysis and the Warburg effect by estrogen-related receptors. Oncogene 32:2079–2086PubMedCrossRefGoogle Scholar
  50. Cairns RA, Harris IS, Mak TW (2011) Regulation of cancer cell metabolism. Nat Rev Cancer 11:85–95PubMedCrossRefGoogle Scholar
  51. Cantorna MT, Nashold FE, Hayes CE (1995) Vitamin A deficiency results in a priming environment conducive for Th1 cell development. Eur J Immunol 25:1673–1679PubMedCrossRefGoogle Scholar
  52. Cao Y, Li H, Liu H, Zheng C, Ji H, Liu X (2010) The serine/threonine kinase LKB1 controls thymocyte survival through regulation of AMPK activation and Bcl-XL expression. Cell Res 20:99–108PubMedCrossRefGoogle Scholar
  53. Cao Y, Li H, Liu H, Zhang M, Hua Z, Ji H, Liu X (2011) LKB1 regulates TCR-mediated PLCγ1 activation and thymocyte positive selection. EMBO J. 30:2083–2093PubMedPubMedCentralCrossRefGoogle Scholar
  54. Cao Y, Rathmell JC, Macintyre AN (2014) Metabolic reprogramming towards aerobic glycolysis correlates with greater proliferative ability and resistance to metabolic inhibition in CD8 versus CD4 T cells. PLoS One 9(8):e104104PubMedPubMedCentralCrossRefGoogle Scholar
  55. Carr EL, Kelman A, Wu GS, Gopaul R, Senkevitch E, Aghvanyan A, Turay AM, Frauwirth KA (2010) Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J Immunol 185:1037–1044PubMedPubMedCentralCrossRefGoogle Scholar
  56. Cassatella MA (1999) Neutrophil-derived proteins: selling cytokines by the pound. Adv Immunol 73:369–509PubMedCrossRefGoogle Scholar
  57. Castrillo A, Joseph SB, Vaidya SA, Haberland M, Fogelman AM, Cheng G, Tontonoz P (2003) Crosstalk between LXR and toll-like receptor signaling mediates bacterial and viral antagonism of cholesterol metabolism. Mol Cell 12:805–816PubMedCrossRefGoogle Scholar
  58. Chabes A, Thelander L (2000) Controlled protein degradation regulates ribonucleotide reductase activity in proliferating mammalian cells during the normal cell cycle and in response to DNA damage and replication blocks. J Biol Chem 275:17747–17753PubMedCrossRefGoogle Scholar
  59. Chakravarty N (1968) Further observations on the inhibition of histamine release by 2-deoxyglucose. Acta Physiologica 72(4):425–432CrossRefGoogle Scholar
  60. Chakravarthy MV, Lodhi IJ, Yin L, Malapaka RR, Xu HE, Turk J, Semenkovich CF (2009) Identification of a physiologically relevant endogenous ligand for PPARα in liver. Cell 138:476–488PubMedPubMedCentralCrossRefGoogle Scholar
  61. Cham CM, Gajewski TF (2005) Glucose availability regulates IFN-γ production and p70S6 kinase activation in CD8+ effector T cells. J Immunol 174:4670–4677PubMedCrossRefGoogle Scholar
  62. Chan KL, Pillon NJ, Sivaloganathan DM, Costford SR, Liu Z, Théret M, Chazaud B, Klip A (2015) Palmitoleate reverses high fat-induced proinflammatory macrophage polarization via AMP-activated protein kinase (AMPK). J Biol Chem 290:16979–16988PubMedPubMedCentralCrossRefGoogle Scholar
  63. Chandra RK (1990) Micronutrients and immune functions. Ann NY Acad Sci 587:9–16PubMedCrossRefGoogle Scholar
  64. Chandra RK (1997) Nutrition and the immune system: an introduction. Am J Clin Nutr 66:460S–463SPubMedCrossRefGoogle Scholar
  65. Chang SH, Chung Y, Dong C (2010) Vitamin D suppresses Th17 cytokine production by inducing C/EBP homologous protein (CHOP) expression. J Biol Chem 285:38751–38755PubMedPubMedCentralCrossRefGoogle Scholar
  66. Chang CH, Curtis JD, Maggi LB, Faubert B, Villarino AV, O’Sullivan D, Huang SC, van der Windt GJ, Blagih J, Qiu J, Weber JD (2013) Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153:1239–1251PubMedPubMedCentralCrossRefGoogle Scholar
  67. Chang CH, Qiu J, O’Sullivan D, Buck MD, Noguchi T, Curtis JD, Chen Q, Gindin M, Gubin MM, van der Windt GJ, Tonc E (2015) Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162:1229–1241PubMedPubMedCentralCrossRefGoogle Scholar
  68. Chantranupong L, Wolfson RL, Orozco JM, Saxton RA, Scaria SM, Bar-Peled L, Spooner E, Isasa M, Gygi SP, Sabatini DM (2014) The Sestrins interact with GATOR2 to negatively regulate the amino-acid-sensing pathway upstream of mTORC1. Cell Rep 9:1–8PubMedPubMedCentralCrossRefGoogle Scholar
  69. Chauhan P, Shukla D, Chattopadhyay D, Saha B (2017) Redundant and regulatory roles for Toll-like receptors in Leishmania infection. Clin Exp Immunol 190:167–186. Scholar
  70. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, Liao D, Nagy L, Edwards PA, Curtiss LK, Evans RM (2001) A PPARγ-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell 7:161–171PubMedCrossRefGoogle Scholar
  71. Chen Q, Ross AC (2007) Retinoic acid promotes mouse splenic B cell surface IgG expression and maturation stimulated by CD40 and IL-4. Cell Immunol 249:37–45PubMedPubMedCentralCrossRefGoogle Scholar
  72. Chen C, Pore N, Behrooz A, Ismail-Beigi F, Maity A (2001) Regulation of glut1 mRNA by hypoxia-inducible factor-1 Interaction between H-ras and hypoxia. J Biol Chem 276:9519–9525PubMedCrossRefGoogle Scholar
  73. Chen S, Sims GP, Chen XX, Gu YY, Chen S, Lipsky PE (2007) Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation. J Immunol 179:1634–1647PubMedCrossRefGoogle Scholar
  74. Chi H (2012) Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol 12:325–338PubMedPubMedCentralCrossRefGoogle Scholar
  75. Chow CW, Rincón M, Davis RJ (1999) Requirement for transcription factor NFAT in interleukin-2 expression. Mol Cell Biol 19:2300–2307PubMedPubMedCentralCrossRefGoogle Scholar
  76. Clambey ET, McNamee EN, Westrich JA, Glover LE, Campbell EL, Jedlicka P, de Zoeten EF, Cambier JC, Stenmark KR, Colgan SP, Eltzschig HK (2012) Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa. Proc Natl Acad Sci USA 109:E2784–E2793PubMedPubMedCentralCrossRefGoogle Scholar
  77. Clark RB, Bishop-Bailey D, Estrada-Hernandez T, Hla T, Puddington L, Padula SJ (2000) The nuclear receptor PPARγ and immunoregulation: PPARγ mediates inhibition of helper T cell responses. J Immunol 164:1364–1371PubMedCrossRefGoogle Scholar
  78. Cohen HY, Miller C, Bitterman KJ, Wall NR, Hekking B, Kessler B, Howitz KT, Gorospe M, de Cabo R, Sinclair DA (2004) Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 305:390–392PubMedCrossRefGoogle Scholar
  79. Contreras AV, Torres N, Tovar AR (2013) PPAR-α as a key nutritional and environmental sensor for metabolic adaptation. Adv Nutr 4:439–452PubMedPubMedCentralCrossRefGoogle Scholar
  80. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867PubMedPubMedCentralCrossRefGoogle Scholar
  81. Covarrubias AJ, Aksoylar HI, Yu J, Snyder NW, Worth AJ, Iyer SS, Wang J, Ben-Sahra I, Byles V, Polynne-Stapornkul T, Espinosa EC (2016) Akt-mTORC1 signaling regulates Acly to integrate metabolic input to control of macrophage activation. Elife 5:e11612PubMedPubMedCentralCrossRefGoogle Scholar
  82. Croft M (2009) Control of immunity by the TNFR-related molecule OX40 (CD134). Annu Rev Immunol 28:57–78CrossRefGoogle Scholar
  83. Crompton JG, Sukumar M, Roychoudhuri R, Clever D, Gros A, Eil RL, Tran E, Hanada KI, Yu Z, Palmer DC, Kerkar SP (2015) Akt inhibition enhances expansion of potent tumor-specific lymphocytes with memory cell characteristics. Cancer Res 75:296–305PubMedCrossRefGoogle Scholar
  84. Cunard R, Ricote M, DiCampli D, Archer DC, Kahn DA, Glass CK, Kelly CJ (2002) Regulation of cytokine expression by ligands of peroxisome proliferator activated receptors. J Immunol 168:2795–2802PubMedCrossRefGoogle Scholar
  85. Curiel R, Akin EA, Beaulieu G, DePalma L, Hashefi M (2011) PET/CT imaging in systemic lupus erythematosus. Ann NY Acad Sci 1228:71–80PubMedCrossRefGoogle Scholar
  86. Daitoku H, Sakamaki JI, Fukamizu A (2011) Regulation of FoxO transcription factors by acetylation and protein–protein interactions. BBA Mol Cell Res 1813:1954–1960Google Scholar
  87. Dang CV (2013) MYC, metabolism, cell growth, and tumorigenesis. CSH Persp Med 3:a014217Google Scholar
  88. Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR, Luo W (2011) Control of TH17/Treg balance by hypoxia-inducible factor 1. Cell 146:772–784PubMedPubMedCentralCrossRefGoogle Scholar
  89. Daniëls VW, Smans K, Royaux I, Chypre M, Swinnen JV, Zaidi N (2014) Cancer cells differentially activate and thrive on de novo lipid synthesis pathways in a low-lipid environment. PLoS One 9:e106913PubMedPubMedCentralCrossRefGoogle Scholar
  90. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, Mncube Z (2006) PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 443:350–354PubMedCrossRefGoogle Scholar
  91. De Pergola G, Silvestris F (2013) Obesity as a major risk factor for cancer. J Obesity:291546.
  92. DeBose-Boyd RA (2008) Feedback regulation of cholesterol synthesis: sterol-accelerated ubiquitination and degradation of HMG CoA reductase. Cell Res 18:609–621PubMedPubMedCentralCrossRefGoogle Scholar
  93. Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL, Xiao B, Worley PF, Kozma SC, Powell JD (2009) The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30:832–844PubMedPubMedCentralCrossRefGoogle Scholar
  94. Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ, Horton MR, Xiao B, Worley PF, Powell JD (2011) The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 12:295–303PubMedPubMedCentralCrossRefGoogle Scholar
  95. den Besten G, van Eunen K, Groen AK, Venema K, Reijngoud DJ, Bakker BM (2013) The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism. J Lipid Res 54:2325–2340CrossRefGoogle Scholar
  96. Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Rev 20:649–688Google Scholar
  97. Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W (1996) The PPARα–leukotriene B4 pathway to inflammation control. Nature 384:39PubMedCrossRefGoogle Scholar
  98. Dijkers PF, Medema RH, Pals C, Banerji L, Thomas NS, Lam EW, Burgering BM, Raaijmakers JA, Lammers JW, Koenderman L, Coffer PJ (2000) Forkhead transcription factor FKHR-L1 modulates cytokine-dependent transcriptional regulation of p27KIP1. Mol Cell Biol 20:9138–9148PubMedPubMedCentralCrossRefGoogle Scholar
  99. Doedens AL, Phan AT, Stradner MH, Fujimoto JK, Nguyen JV, Yang E, Johnson RS, Goldrath AW (2013) Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen. Nat Immunol 14:1173–1182PubMedPubMedCentralCrossRefGoogle Scholar
  100. Dong XY, Tang SQ, Chen JD (2012) Dual functions of Insig proteins in cholesterol homeostasis. Lipids Health Dis 11:173PubMedPubMedCentralCrossRefGoogle Scholar
  101. Doyle AG, Herbein G, Montaner LJ, Minty AJ, Caput D, Ferrara P, Gordon S (1994) Interleukin-13 alters the activation state of murine macrophages in vitro: comparison with interleukin-4 and interferon-γ. Eur J Immunol 24:1441–1445PubMedCrossRefGoogle Scholar
  102. Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik T (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464:1357–1361PubMedPubMedCentralCrossRefGoogle Scholar
  103. Durham NM, Nirschl CJ, Jackson CM, Elias J, Kochel CM, Anders RA, Drake CG (2014) Lymphocyte Activation Gene 3 (LAG-3) modulates the ability of CD4 T-cells to be suppressed in vivo. PLoS One 9:e109080PubMedPubMedCentralCrossRefGoogle Scholar
  104. Düvel K, Yecies JL, Menon S, Raman P, Lipovsky AI, Souza AL, Triantafellow E, Ma Q, Gorski R, Cleaver S, Vander Heiden MG (2010) Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 39:171–183PubMedPubMedCentralCrossRefGoogle Scholar
  105. Eckel RH (1997) Obesity and heart disease. Circulation 96:3248–3250PubMedCrossRefGoogle Scholar
  106. Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, Asara JM (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331:456–461PubMedCrossRefGoogle Scholar
  107. Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH, Plas DR, Zhuang H, Cinalli RM, Alavi A, Rudin CM, Thompson CB (2004) Akt stimulates aerobic glycolysis in cancer cells. Cancer Res 64:3892–3899PubMedCrossRefGoogle Scholar
  108. Emanuelle S, Hossain MI, Moller IE, Pedersen HL, Meene AM, Doblin MS, Koay A, Oakhill JS, Scott JW, Willats WG, Kemp BE (2015) SnRK1 from Arabidopsis thaliana is an atypical AMPK. Plant J 82:183–192PubMedCrossRefGoogle Scholar
  109. Eriksson S, Gräslund A, Skog S, Thelander L, Tribukait B (1984) Cell cycle-dependent regulation of mammalian ribonucleotide reductase. The S phase-correlated increase in subunit M2 is regulated by de novo protein synthesis. J Biol Chem 259:11695–11700PubMedGoogle Scholar
  110. Everts B, Amiel E, van der Windt GJ, Freitas TC, Chott R, Yarasheski KE, Pearce EL, Pearce EJ (2012) Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells. Blood 120:1422–1431PubMedPubMedCentralCrossRefGoogle Scholar
  111. Everts B, Amiel E, Huang SC, Smith AM, Chang CH, Lam WY, Redmann V, Freitas TC, Blagih J, Van Der Windt GJ, Artyomov MN (2014) TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKε supports the anabolic demands of dendritic cell activation. Nat Immunol 15:323–332PubMedPubMedCentralCrossRefGoogle Scholar
  112. Fajardo AM, Piazza GA, Tinsley HN (2014) The role of cyclic nucleotide signaling pathways in cancer: targets for prevention and treatment. Cancers 6:436–458PubMedPubMedCentralCrossRefGoogle Scholar
  113. Fajas L, Egler V, Reiter R, Miard S, Lefebvre AM, Auwerx J (2003) PPARγ controls cell proliferation and apoptosis in an RB-dependent manner. Oncogene 22:4186–4193PubMedCrossRefGoogle Scholar
  114. Fang X, Yu SX, Lu Y, Bast RC, Woodgett JR, Mills GB (2000) Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc Natl Acad Sci USA 97:11960–11965PubMedPubMedCentralCrossRefGoogle Scholar
  115. Faubert B, Boily G, Izreig S, Griss T, Samborska B, Dong Z, Dupuy F, Chambers C, Fuerth BJ, Viollet B, Mamer OA (2013) AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo. Cell Metab 17:113–124PubMedCrossRefGoogle Scholar
  116. Fernández-Riejos P, Najib S, Santos-Alvarez J, Martín-Romero C, Pérez-Pérez A, González-Yanes C, Sánchez-Margalet V (2010) Role of leptin in the activation of immune cells. Mediators Inflamm.
  117. Ferrannini E, DeFronzo RA (2015) Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J 36:2288–2296PubMedCrossRefGoogle Scholar
  118. Fingar DC, Richardson CJ, Tee AR, Cheatham L, Tsou C, Blenis J (2004) mTOR controls cell cycle progression through its cell growth effectors S6K1 and 4E-BP1/eukaryotic translation initiation factor 4E. Mol Cell Biol 24:200–216PubMedPubMedCentralCrossRefGoogle Scholar
  119. Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, Gottfried E, Schwarz S, Rothe G, Hoves S, Renner K (2007) Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 109:3812–3819PubMedCrossRefGoogle Scholar
  120. Flannagan RS, Heit B, Heinrichs DE (2016) Intracellular replication of Staphylococcus aureus in mature phagolysosomes in macrophages precedes host cell death, and bacterial escape and dissemination. Cell Microbiol 18:514–535PubMedCrossRefGoogle Scholar
  121. Fletcher M, Ramirez ME, Sierra RA, Raber P, Thevenot P, Al-Khami AA, Sanchez-Pino D, Hernandez C, Wyczechowska DD, Ochoa AC, Rodriguez PC (2015) L-Arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells. Cancer Res 75:275–283PubMedCrossRefGoogle Scholar
  122. Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol 16:4604–4613PubMedPubMedCentralCrossRefGoogle Scholar
  123. Fox CJ, Hammerman PS, Thompson CB (2005) Fuel feeds function: energy metabolism and the T-cell response. Nat Rev Immunol 5:844–852PubMedCrossRefGoogle Scholar
  124. Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, Elstrom RL, June CH, Thompson CB (2002) The CD28 signaling pathway regulates glucose metabolism. Immunity 16:769–777PubMedCrossRefGoogle Scholar
  125. Freedman SJ, Sun ZY, Poy F, Kung AL, Livingston DM, Wagner G, Eck MJ (2002) Structural basis for recruitment of CBP/p300 by hypoxia-inducible factor-1α. Proc Natl Acad Sci USA 99:5367–5372PubMedPubMedCentralCrossRefGoogle Scholar
  126. Freemerman AJ, Johnson AR, Sacks GN, Milner JJ, Kirk EL, Troester MA, Macintyre AN, Goraksha-Hicks P, Rathmell JC, Makowski L (2014) Metabolic reprogramming of macrophages glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. J Biol Chem 289:7884–7896PubMedPubMedCentralCrossRefGoogle Scholar
  127. Frieden TR (2015) The future of public health. N Engl J Med 373:1748–1754PubMedCrossRefGoogle Scholar
  128. Fujishima S, Hoffman AR, Vu T, Kim KJ, Zheng H, Daniel D, Kim Y, Wallace EF, Larrick JW, Raffin TA (1993) Regulation of neutrophil interleukin 8 gene expression and protein secretion by LPS, TNF-α, and IL-1β. J Cell Physiol 154:478–485PubMedCrossRefGoogle Scholar
  129. Fukuzumi M, Shinomiya H, Shimizu Y, Ohishi K, Utsumi S (1996) Endotoxin-induced enhancement of glucose influx into murine peritoneal macrophages via GLUT1. Infect Immun 64:108–112PubMedPubMedCentralGoogle Scholar
  130. Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M (2013) Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504:446–450PubMedCrossRefGoogle Scholar
  131. Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14:1014–1022PubMedPubMedCentralCrossRefGoogle Scholar
  132. Galli SJ, Kalesnikoff J, Grimbaldeston MA, Piliponsky AM, Williams CM, Tsai M (2005) Mast cells as “tunable” effector and immunoregulatory cells: recent advances. Annu Rev Immunol 23:749–786PubMedCrossRefGoogle Scholar
  133. Galván-Peña S, O’Neill LA (2014) Metabolic reprograming in macrophage polarization. Front Immunol 5:420PubMedPubMedCentralGoogle Scholar
  134. Ganeshan K, Chawla A (2014) Metabolic regulation of immune responses. Annu Rev Immunol 32:609–634PubMedPubMedCentralCrossRefGoogle Scholar
  135. Gao P, Tchernyshyov I, Chang TC, Lee YS, Kita K, Ochi T, Zeller KI, De Marzo AM, Van Eyk JE, Mendell JT, Dang CV (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458:762–765PubMedPubMedCentralCrossRefGoogle Scholar
  136. Garçon F, Patton DT, Emery JL, Hirsch E, Rottapel R, Sasaki T, Okkenhaug K (2008) CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer. Blood 111:1464–1471PubMedCrossRefGoogle Scholar
  137. Garedew A, Henderson SO, Moncada S (2010) Activated macrophages utilize glycolytic ATP to maintain mitochondrial membrane potential and prevent apoptotic cell death. Cell Death Diff 17:1540–1550CrossRefGoogle Scholar
  138. Gatza E, Wahl DR, Opipari AW, Sundberg TB, Reddy P, Liu C, Glick GD, Ferrara JL (2011) Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease. Sci Transl Med 3:67ra8PubMedPubMedCentralCrossRefGoogle Scholar
  139. Gazzerro P, Proto MC, Gangemi G, Malfitano AM, Kigali E, Pisanti S, Santoro A, Laezza C, Bifulco M (2012) Pharmacological actions of statins: a critical appraisal in the management of cancer. Pharmacol Rev 64:102–146PubMedCrossRefGoogle Scholar
  140. Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K (2010) Development of monocytes, macrophages, and dendritic cells. Science 327:656–661PubMedPubMedCentralCrossRefGoogle Scholar
  141. Gerriets VA, Rathmell JC (2012) Metabolic pathways in T cell fate and function. Trends Immunol 33:168–173PubMedPubMedCentralCrossRefGoogle Scholar
  142. Geyeregger R, Shehata M, Zeyda M, Kiefer FW, Stuhlmeier KM, Porpaczy E, Zlabinger GJ, Jäger U, Stulnig TM (2009) Liver X receptors interfere with cytokine-induced proliferation and cell survival in normal and leukemic lymphocytes. J Leukoc Biol 86:1039–1048PubMedCrossRefGoogle Scholar
  143. Ghaemi-Oskouie F, Shi Y (2011) The role of uric acid as an endogenous danger signal in immunity and inflammation. Curr Rheumatol Rep 13:160–166PubMedPubMedCentralCrossRefGoogle Scholar
  144. Ghesquiere B, Wong BW, Kuchnio A, Carmeliet P (2014) Metabolism of stromal and immune cells in health and disease. Nature 511:167–176PubMedCrossRefGoogle Scholar
  145. Gigoux M, Shang J, Pak Y, Xu M, Choe J, Mak TW, Suh WK (2009) Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase. Proc Natl Acad Sci USA 106:20371–20376PubMedPubMedCentralCrossRefGoogle Scholar
  146. Gingras AC, Raught B, Gygi SP, Niedzwiecka A, Miron M, Burley SK, Polakiewicz RD, Wyslouch-Cieszynska A, Aebersold R, Sonenberg N (2001) Hierarchical phosphorylation of the translation inhibitor 4E-BP1. Genes Dev 15:2852–2864PubMedPubMedCentralCrossRefGoogle Scholar
  147. Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845PubMedPubMedCentralCrossRefGoogle Scholar
  148. Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35PubMedCrossRefGoogle Scholar
  149. Gordon S, Martinez FO (2010) Alternative activation of macrophages: mechanism and functions. Immunity 32:593–604PubMedCrossRefGoogle Scholar
  150. Goverse G, Labao-Almeida C, Ferreira M, Molenaar R, Wahlen S, Konijn T, Koning J, Veiga-Fernandes H, Mebius RE (2016) Vitamin A controls the presence of RORγ+ innate lymphoid cells and lymphoid tissue in the small intestine. J Immunol 196:5148–5155PubMedCrossRefGoogle Scholar
  151. Gracias DT, Boesteanu AC, Fraietta JA, Hope JL, Carey AJ, Mueller YM, Kawalekar OU, Fike AJ, June CH, Katsikis PD (2016) Phosphatidylinositol 3-kinase p110δ isoform regulates CD8+ T cell responses during acute viral and intracellular bacterial infections. J Immunol 196:1186–1198PubMedPubMedCentralCrossRefGoogle Scholar
  152. Greene ME, Blumberg B, McBride OW, Yi HF, Kronquist K, Kwan K, Hsieh L, Greene G, Nimer SD (1995) Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Exp 4:281–299Google Scholar
  153. Greer EL, Dowlatshahi D, Banko MR, Villen J, Hoang K, Blanchard D, Gygi SP, Brunet A (2007) An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans. Curr Biol 17:1646–1656PubMedPubMedCentralCrossRefGoogle Scholar
  154. Gubser PM, Bantug GR, Razik L, Fischer M, Dimeloe S, Hoenger G, Durovic B, Jauch A, Hess C (2013) Rapid effector function of memory CD8+ T cells requires an immediate-early glycolytic switch. Nat Immunol 14:1064–1072PubMedCrossRefGoogle Scholar
  155. Guertin DA, Sabatini DM (2007) Defining the role of mTOR in cancer. Cancer Cell 12:9–22PubMedCrossRefGoogle Scholar
  156. Guimarães-Costa AB, Nascimento MT, Froment GS, Soares RP, Morgado FN, Conceição-Silva F, Saraiva EM (2009) Leishmania amazonensis promastigotes induce and are killed by neutrophil extracellular traps. Proc Natl Acad Sci USA 106:6748–6753PubMedPubMedCentralCrossRefGoogle Scholar
  157. Guo Y, Zhang Y, Hong K, Luo F, Gu Q, Lu N, Bai A (2014) AMPK inhibition blocks ROS-NFκB signaling and attenuates endotoxemia-induced liver injury. PLoS One 9:e86881PubMedPubMedCentralCrossRefGoogle Scholar
  158. Guppy M, Greiner E, Brand K (1993) The role of the Crabtree effect and an endogenous fuel in the energy metabolism of resting and proliferating thymocytes. FEBS J 212:95–99Google Scholar
  159. Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, Turk BE, Shaw RJ (2008) AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 30:214–226PubMedPubMedCentralCrossRefGoogle Scholar
  160. Hahn-Windgassen A, Nogueira V, Chen CC, Skeen JE, Sonenberg N, Hay N (2005) Akt activates the mammalian target of rapamycin by regulating cellular ATP level and AMPK activity. J Biol Chem 280:32081–32089PubMedCrossRefGoogle Scholar
  161. Hamilton SR, O’Donnell JB, Hammet A, Stapleton D, Habinowski SA, Means AR, Kemp BE, Witters LA (2002) AMP-activated protein kinase kinase: detection with recombinant AMPK α1 subunit. Biochem Biophy Res Commun 293:892–898CrossRefGoogle Scholar
  162. Hampton MB, Kettle AJ, Winterbourn CC (1998) Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing. Blood 92:3007–3017PubMedGoogle Scholar
  163. Han JM, Jeong SJ, Park MC, Kim G, Kwon NH, Kim HK, Ha SH, Ryu SH, Kim S (2012) Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway. Cell 149:410–424PubMedCrossRefGoogle Scholar
  164. Hancock T, Takigawa I, Mamitsuka H (2010) Mining metabolic pathways through gene expression. Bioinformatics 26:2128–2135PubMedPubMedCentralCrossRefGoogle Scholar
  165. Hand TW, Cui W, Jung YW, Sefik E, Joshi NS, Chandele A, Liu Y, Kaech SM (2010) Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival. Proc Natl Acad Sci USA 107:16601–16606PubMedPubMedCentralCrossRefGoogle Scholar
  166. Harada H, Itasaka S, Kizaka-Kondoh S, Shibuya K, Morinibu A, Shinomiya K, Hiraoka M (2009) The Akt/mTOR pathway assures the synthesis of HIF-1α protein in a glucose-and reoxygenation-dependent manner in irradiated tumors. J Biol Chem 284:5332–5342PubMedCrossRefGoogle Scholar
  167. Hardie DG (2002) A homologue of AMP-activated protein kinase in Drosophila melanogaster is sensitive to AMP and is activated by ATP depletion. Biochem J 367:179–186PubMedPubMedCentralCrossRefGoogle Scholar
  168. Hardie DG, Hawley SA (2001) AMP-activated protein kinase: the energy charge hypothesis revisited. BioEssays 23:1112–1119PubMedCrossRefGoogle Scholar
  169. Hardie DG, Scott JW, Pan DA, Hudson ER (2003) Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett 546:113–120PubMedCrossRefGoogle Scholar
  170. Harding FA, JG MA, Gross JA, Raulet DH, Allison JP (1992) CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature 356:607–609PubMedCrossRefGoogle Scholar
  171. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, Ron D (2000) Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 6:1099–1108PubMedCrossRefGoogle Scholar
  172. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, Sadri N, Yun C, Popko B, Paules R, Stojdl DF (2003) An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 11:619–633PubMedCrossRefGoogle Scholar
  173. Harris SG, Phipps RP (2001) The nuclear receptor PPAR gamma is expressed by mouse T lymphocytes and PPAR gamma agonists induce apoptosis. Eur J Immunol 31:1098–1105PubMedCrossRefGoogle Scholar
  174. Haschemi A, Kosma P, Gille L, Evans CR, Burant CF, Starkl P, Knapp B, Haas R, Schmid JA, Jandl C, Amir S (2012) The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab 15:813–826PubMedPubMedCentralCrossRefGoogle Scholar
  175. Hawley SA, Davison M, Woods A, Davies SP, Beri RK, Carling D, Hardie DG (1996) Characterization of the AMP-activated protein kinase kinase from rat liver and identification of threonine 172 as the major site at which it phosphorylates AMP-activated protein kinase. J Biol Chem 271:27879–27887PubMedCrossRefGoogle Scholar
  176. Hawley SA, Boudeau J, Reid JL, Mustard KJ, Udd L, Mäkelä TP, Alessi DR, Hardie DG (2003) Complexes between the LKB1 tumor suppressor, STRADα/β and MO25α/β are upstream kinases in the AMP-activated protein kinase cascade. J Biol 2:28PubMedPubMedCentralCrossRefGoogle Scholar
  177. Haxhinasto S, Mathis D, Benoist C (2008) The AKT–mTOR axis regulates de novo differentiation of CD4+ Foxp3+ cells. J Exp Med 205:565–574PubMedPubMedCentralCrossRefGoogle Scholar
  178. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18:1926–1945PubMedCrossRefGoogle Scholar
  179. Hayashi K, Jutabha P, Endou H, Sagara H, Anzai N (2013) LAT1 is a critical transporter of essential amino acids for immune reactions in activated human T cells. J Immunol 191:4080–4085PubMedCrossRefGoogle Scholar
  180. Hedbacker K, Carlson M (2008) SNF1/AMPK pathways in yeast. Front Biosci: J Virtual Lib 13:2408CrossRefGoogle Scholar
  181. Heine G, Anton K, Henz BM, Worm M (2002) 1α, 25-dihydroxyvitamin D3 inhibits anti-CD40 plus IL-4-mediated IgE production in vitro. Eur J Immunol 32:3395–3404PubMedGoogle Scholar
  182. Hemmi H, Akira S (2005) TLR signalling and the function of dendritic cells. Mech Epithelial Def 86:120–135CrossRefGoogle Scholar
  183. Henao-Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP (2012) Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482:179–185PubMedPubMedCentralCrossRefGoogle Scholar
  184. Henin N, Vincent MF, Gruber HE, Van den Berghe G (1995) Inhibition of fatty acid and cholesterol synthesis by stimulation of AMP-activated protein kinase. FASEB J 9:541–546PubMedCrossRefGoogle Scholar
  185. Hershey JW (1991) Translational control in mammalian cells. Annu Rev Biochem 60:717–755PubMedCrossRefGoogle Scholar
  186. Hinnebusch AG (2005) Translational regulation of GCN4 and the general amino acid control of yeast. Annu Rev Microbiol 59:407–450PubMedCrossRefGoogle Scholar
  187. Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, Tsui YC, Cui G, Micevic G, Perales JC, Kleinstein SH (2015) Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162:1217–1228PubMedPubMedCentralCrossRefGoogle Scholar
  188. Hoag KA, Nashold FE, Goverman J, Hayes CE (2002) Retinoic acid enhances the T helper 2 cell development that is essential for robust antibody responses through its action on antigen-presenting cells. J Nutr 132:3736–3739PubMedCrossRefGoogle Scholar
  189. Hoebe K, Janssen E, Beutler B (2004) The interface between innate and adaptive immunity. Nat Immunol 5:971–974PubMedCrossRefGoogle Scholar
  190. Hoeffel G, Wang Y, Greter M, See P, Teo P, Malleret B, Leboeuf M, Low D, Oller G, Almeida F, Choy SH (2012) Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J Exp Med 209:1167–1181PubMedPubMedCentralCrossRefGoogle Scholar
  191. Hong SP, Leiper FC, Woods A, Carling D, Carlson M (2003) Activation of yeast Snf1 and mammalian AMP-activated protein kinase by upstream kinases. Proc Natl Acad Sci USA 100:8839–8843PubMedPubMedCentralCrossRefGoogle Scholar
  192. Horton JD, Goldstein JL, Brown MS (2002) SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109:1125–1131PubMedPubMedCentralCrossRefGoogle Scholar
  193. Hotamisligil GS (2006) Inflammation and metabolic disorders. Nature 444:860–867PubMedCrossRefGoogle Scholar
  194. Høyer-Hansen M, Bastholm L, Szyniarowski P, Campanella M, Szabadkai G, Farkas T, Bianchi K, Fehrenbacher N, Elling F, Rizzuto R, Mathiasen IS (2007) Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-β, and Bcl-2. Mol Cell 25:193–205PubMedCrossRefGoogle Scholar
  195. Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC (2003) Differential roles of hypoxia-inducible factor 1α (HIF-1α) and HIF-2α in hypoxic gene regulation. Mol Cell Biol 23:9361–9374PubMedPubMedCentralCrossRefGoogle Scholar
  196. Hua X, Thompson CB (2001) Quiescent T cells: actively maintaining inactivity. Nat Immunol 2:1097–1098PubMedCrossRefGoogle Scholar
  197. Huang BP, Lin CH, Chen HM, Lin JT, Cheng YF, Kao SH (2015) AMPK activation inhibits expression of proinflammatory mediators through downregulation of PI3K/p38 MAPK and NF-κB signaling in murine macrophages. DNA Cell Biol 34:133–141PubMedCrossRefGoogle Scholar
  198. Hubbard VM, Valdor R, Patel B, Singh R, Cuervo AM, Macian F (2010) Macroautophagy regulates energy metabolism during effector T-cell activation. J Immunol 185:7349–7357PubMedPubMedCentralCrossRefGoogle Scholar
  199. Hudson CC, Liu M, Chiang GG, Otterness DM, Loomis DC, Kaper F, Giaccia AJ, Abraham RT (2002) Regulation of hypoxia-inducible factor 1α expression and function by the mammalian target of rapamycin. Mol Cell Biol 22:7004–7014PubMedPubMedCentralCrossRefGoogle Scholar
  200. Inoki K, Li Y, Zhu T, Wu J, Guan KL (2002) TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 4:648–657PubMedCrossRefGoogle Scholar
  201. Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY (2006) TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126:955–968PubMedCrossRefGoogle Scholar
  202. Inoki K, Kim J, Guan KL (2012) AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol 52:381–400PubMedCrossRefGoogle Scholar
  203. Iyer SS, Chatraw JH, Tan WG, Wherry EJ, Becker TC, Ahmed R, Kapasi ZF (2012) Protein energy malnutrition impairs homeostatic proliferation of memory CD8 T cells. J Immunol 188:77–84PubMedCrossRefGoogle Scholar
  204. Jablonski KA, Amici SA, Webb LM, de Dios Ruiz-Rosado J, Popovich PG, Partida-Sanchez S, Guerau-de-Arellano M (2015) Novel markers to delineate murine M1 and M2 macrophages. PLoS One 10:e0145342PubMedPubMedCentralCrossRefGoogle Scholar
  205. Jacinto E, Loewith R, Schmidt A, Lin S, Rüegg MA, Hall A, Hall MN (2004) Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat Cell Biol 6:1122–1128PubMedCrossRefGoogle Scholar
  206. Jacobs SR, Herman CE, MacIver NJ, Wofford JA, Wieman HL, Hammen JJ, Rathmell JC (2008) Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J Immunol 180:4476–4486PubMedPubMedCentralCrossRefGoogle Scholar
  207. Jelkmann W (2011) Regulation of erythropoietin production. J Physiol 589:1251–1258PubMedCrossRefGoogle Scholar
  208. Jeon SH, Lee MY, Kim SJ, Joe SG, Kim GB, Kim IS, Kim NS, Hong CU, Kim SZ, Kim JS, Kang HS (2007) Taurine increases cell proliferation and generates an increase in [Mg2+] I accompanied by ERK 1/2 activation in human osteoblast cells. FEBS Lett 581:5929–5934PubMedCrossRefGoogle Scholar
  209. Jewell JL, Kim YC, Russell RC, Yu FX, Park HW, Plouffe SW, Tagliabracci VS, Guan KL (2015) Differential regulation of mTORC1 by leucine and glutamine. Science 347:194–198PubMedPubMedCentralCrossRefGoogle Scholar
  210. Jhun BS, Oh YT, Lee JY, Kong Y, Yoon KS, Kim SS, Baik HH, Ha J, Kang I (2005) AICAR suppresses IL-2 expression through inhibition of GSK-3 phosphorylation and NF-AT activation in Jurkat T cells. Biochem Biophys Res Commun 332:339–346PubMedCrossRefGoogle Scholar
  211. Jing E, Gesta S, Kahn CR (2007) SIRT2 regulates adipocyte differentiation through FOXO1 acetylation/deacetylation. Cell Metab 6:105–114PubMedPubMedCentralCrossRefGoogle Scholar
  212. Johansen T (1979) Adenosine triphosphate levels during anaphylactic histamine release in rat mast cells in vitro. Effects of glycolytic and respiratory inhibitors. Eur J Pharmacol 58:107–115PubMedCrossRefGoogle Scholar
  213. Johnson AR, Justin Milner J, Makowski L (2012) The inflammation highway: metabolism accelerates inflammatory traffic in obesity. Immunol Rev 249:218–238PubMedPubMedCentralCrossRefGoogle Scholar
  214. Jones RG, Thompson CB (2007) Revving the engine: signal transduction fuels T cell activation. Immunity 27:173–178PubMedCrossRefGoogle Scholar
  215. Jones DC, Manning BM, Daynes RA (2002) A role for the peroxisome proliferator-activated receptor α in T-cell physiology and ageing immunobiology. Proc Nutr Soc 61:363–369PubMedCrossRefGoogle Scholar
  216. Joshi MB, Lad A, Prasad B, Alevoor S, Balakrishnan A, Ramachandra L, Satyamoorthy K (2013) High glucose modulates IL-6 mediated immune homeostasis through impeding neutrophil extracellular trap formation. FEBS Lett 587:2241–2246PubMedCrossRefGoogle Scholar
  217. Jump DB (2004) Fatty acid regulation of gene transcription. Crit Rev Clin Lab Sci 41:41–78PubMedCrossRefGoogle Scholar
  218. Jung CH, Ro SH, Cao J, Otto NM, Kim DH (2010) mTOR regulation of autophagy. FEBS Lett 584:1287–1295PubMedPubMedCentralCrossRefGoogle Scholar
  219. Kaesler S, Sobiesiak M, Kneilling M, Volz T, Kempf WE, Lang PA, Lang KS, Wieder T, Heller-Stilb B, Warskulat U, Häussinger D (2012) Effective T-cell recall responses require the taurine transporter Taut. Eur J Immunol 42:831–841PubMedCrossRefGoogle Scholar
  220. Kamphorst JJ, Cross JR, Fan J, de Stanchina E, Mathew R, White EP, Thompson CB, Rabinowitz JD (2013) Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids. Proc Natl Acad Sci USA 110:8882–8887PubMedPubMedCentralCrossRefGoogle Scholar
  221. Kane LP, Weiss A (2003) The PI-3 kinase/Akt pathway and T cell activation: pleiotropic pathways downstream of PIP3. Immunol Rev 192:7–20PubMedCrossRefGoogle Scholar
  222. Kawai T, Akira S (2009) The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol 21:317–337PubMedPubMedCentralCrossRefGoogle Scholar
  223. Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–650PubMedCrossRefGoogle Scholar
  224. Keating SE, Zaiatz-Bittencourt V, Loftus RM, Keane C, Brennan K, Finlay DK, Gardiner CM (2016) Metabolic reprogramming supports IFN-γ production by CD56bright NK cells. J Immunol 196:2552–2560PubMedCrossRefGoogle Scholar
  225. Kelly B, O’Neill LA (2015) Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res 25:771–784PubMedPubMedCentralCrossRefGoogle Scholar
  226. Keppel MP, Saucier N, Mah AY, Vogel TP, Cooper MA (2015) Activation-specific metabolic requirements for NK cell IFN-γ production. J Immunol 194:1954–1962PubMedPubMedCentralCrossRefGoogle Scholar
  227. Kerdiles YM, Beisner DR, Tinoco R, Dejean AS, Castrillon DH, DePinho RA, Hedrick SM (2009) Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat Immunol 10:176–184PubMedPubMedCentralCrossRefGoogle Scholar
  228. Kersten S (2014) Integrated physiology and systems biology of PPARα. Mol Metabol 3:354–371CrossRefGoogle Scholar
  229. Kidani Y, Elsaesser H, Hock MB, Vergnes L, Williams KJ, Argus JP, Marbois BN, Komisopoulou E, Wilson EB, Osborne TF, Graeber TG (2013) Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat Immunol 14:489–499PubMedPubMedCentralCrossRefGoogle Scholar
  230. Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006a) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3:177–185PubMedCrossRefGoogle Scholar
  231. Kim KY, Kim JK, Han SH, Lim JS, Kim KI, Cho DH, Lee MS, Lee JH, Yoon DY, Yoon SR, Chung JW (2006b) Adiponectin is a negative regulator of NK cell cytotoxicity. J Immunol 176:5958–5964PubMedCrossRefGoogle Scholar
  232. Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13:132–141PubMedPubMedCentralCrossRefGoogle Scholar
  233. Kim MV, Ouyang W, Liao W, Zhang MQ, Li MO (2013a) The transcription factor Foxo1 controls central-memory CD8+ T cell responses to infection. Immunity 39:286–297PubMedCrossRefGoogle Scholar
  234. Kim SG, Buel GR, Blenis J (2013b) Nutrient regulation of the mTOR complex 1 signaling pathway. Mol Cells 35:463–473PubMedPubMedCentralCrossRefGoogle Scholar
  235. Kim MH, Taparowsky EJ, Kim CH (2015) Retinoic acid differentially regulates the migration of innate lymphoid cell subsets to the gut. Immunity 43:107–119PubMedPubMedCentralCrossRefGoogle Scholar
  236. Kliewer SA, Umesono K, Noonan DJ, Heyman RA, Evans RM (1992) Convergence of 9-cis retinoic acid and peroxisome proliferator signalling pathways through heterodimer formation of their receptors. Nature 358:771–774PubMedCrossRefGoogle Scholar
  237. Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, Umesono K, Evans RM (1994) Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA 91:7355–7359PubMedPubMedCentralCrossRefGoogle Scholar
  238. Klimova T, Chandel NS (2008) Mitochondrial complex III regulates hypoxic activation of HIF. Cell Death Differ 15:660–666PubMedCrossRefGoogle Scholar
  239. Klotz L, Dani I, Edenhofer F, Nolden L, Evert B, Paul B, Kolanus W, Klockgether T, Knolle P, Diehl L (2007) Peroxisome proliferator-activated receptor γ control of dendritic cell function contributes to development of CD4+ T cell anergy. J Immunol 178:2122–2131PubMedCrossRefGoogle Scholar
  240. Kojima H, Sitkovsky MV, Cascalho M (2003) HIF-1α deficiency perturbs T and B cell functions. Curr Pharm Des 9:1827–1832PubMedCrossRefGoogle Scholar
  241. Kola B (2008) Role of AMP-activated protein kinase in the control of appetite. J Neuroendocrinol 20:942–951PubMedPubMedCentralCrossRefGoogle Scholar
  242. Kolev M, Dimeloe S, Le Friec G, Navarini A, Arbore G, Povoleri GA, Fischer M, Belle R, Loeliger J, Develioglu L, Bantug GR (2015) Complement regulates nutrient influx and metabolic reprogramming during Th1 cell responses. Immunity 42:1033–1047PubMedPubMedCentralCrossRefGoogle Scholar
  243. Kong S, Yeung P, Fang D (2013) The class III histone deacetylase sirtuin 1 in immune suppression and its therapeutic potential in rheumatoid arthritis. J Genet Genomics 40:347–354PubMedPubMedCentralCrossRefGoogle Scholar
  244. Kopf H, Gonzalo M, Howard OZ, Chen X (2007) Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells. Int Pharmacol 7:1819–1824Google Scholar
  245. Kovacic S, Soltys CL, Barr AJ, Shiojima I, Walsh K, Dyck JR (2003) Akt activity negatively regulates phosphorylation of AMP-activated protein kinase in the heart. J Biol Chem 278:39422–39427PubMedCrossRefGoogle Scholar
  246. Kramer PA, Ravi S, Chacko B, Johnson MS, Darley-Usmar VM (2014) A review of the mitochondrial and glycolytic metabolism in human platelets and leukocytes: implications for their use as bioenergetic biomarkers. Redox Biol 2:206–210PubMedPubMedCentralCrossRefGoogle Scholar
  247. Krawczyk CM, Holowka T, Sun J, Blagih J, Amiel E, DeBerardinis RJ, Cross JR, Jung E, Thompson CB, Jones RG, Pearce EJ (2010) Toll-like receptor-induced changes in glycolytic metabolism regulate dendritic cell activation. Blood 115:4742–4749PubMedPubMedCentralCrossRefGoogle Scholar
  248. Kuschak TI, Kuschak BC, Taylor CL, Wright JA, Wiener F, Mai S (2002) c-Myc initiates illegitimate replication of the ribonucleotide reductase R2 gene. Oncogene 21:909PubMedCrossRefGoogle Scholar
  249. Laplante M, Sabatini DM (2009) mTOR signaling at a glance. J Cell Sci 122(20):3589–3594PubMedPubMedCentralCrossRefGoogle Scholar
  250. Larsson C (2006) Protein kinase C and the regulation of the actin cytoskeleton. Cell Signal 18:276–284PubMedCrossRefGoogle Scholar
  251. Lawrence T, Natoli G (2011) Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol 11:750–761PubMedCrossRefGoogle Scholar
  252. LeBleu VS, O’Connell JT, Herrera KN, Wikman H, Pantel K, Haigis MC, De Carvalho FM, Damascena A, Chinen LT, Rocha RM, Asara JM (2014) PGC-1α mediates mitochondrial biogenesis and oxidative phosphorylation in cancer cells to promote metastasis. Nat Cell Biol 16:992–1003PubMedPubMedCentralCrossRefGoogle Scholar
  253. Lee WJ, Kim M, Park HS, Kim HS, Jeon MJ, Oh KS, Koh EH, Won JC, Kim MS, Oh GT, Yoon M (2006) AMPK activation increases fatty acid oxidation in skeletal muscle by activating PPARα and PGC-1. Biochem Biophys Res Commun 340:291–295PubMedCrossRefGoogle Scholar
  254. Lee H, Cho JS, Lambacher N, Lee J, Lee SJ, Lee TH, Gartner A, Koo HS (2008) The Caenorhabditis elegans AMP-activated protein kinase AAK-2 is phosphorylated by LKB1 and is required for resistance to oxidative stress and for normal motility and foraging behavior. J Biol Chem 283(22):14988–14993PubMedPubMedCentralCrossRefGoogle Scholar
  255. Lee K, Gudapati P, Dragovic S, Spencer C, Joyce S, Killeen N, Magnuson MA, Boothby M (2010) Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 32:743–753PubMedPubMedCentralCrossRefGoogle Scholar
  256. Lee JS, Cella M, McDonald KG, Garlanda C, Kennedy GD, Nukaya M, Mantovani A, Kopan R, Bradfield CA, Newberry RD, Colonna M (2012) AHR drives the development of gut ILC22 cells and postnatal lymphoid tissues via pathways dependent on and independent of Notch. Nat Immunol 13:144–151CrossRefGoogle Scholar
  257. Lee JV, Carrer A, Shah S, Snyder NW, Wei S, Venneti S, Worth AJ, Yuan ZF, Lim HW, Liu S, Jackson E (2014) Akt-dependent metabolic reprogramming regulates tumor cell histone acetylation. Cell Metab 20:306–319PubMedPubMedCentralCrossRefGoogle Scholar
  258. Lee JH, Elly C, Park Y, Liu YC (2015) E3 ubiquitin ligase VHL regulates hypoxia-inducible factor-1α to maintain regulatory T cell stability and suppressive capacity. Immunity 42:1062–1074PubMedPubMedCentralCrossRefGoogle Scholar
  259. Lee JH, Cho US, Karin M (2016) Sestrin regulation of TORC1: is Sestrin a leucine sensor? Sci Signal 9:re5PubMedPubMedCentralCrossRefGoogle Scholar
  260. Levring TB, Hansen AK, Nielsen BL, Kongsbak M, von Essen MR, Woetmann A, Ødum N, Bonefeld CM, Geisler C (2012) Activated human CD4+ T cells express transporters for both cysteine and cystine. Sci Rep 2:266PubMedPubMedCentralCrossRefGoogle Scholar
  261. L’homme L, Esser N, Riva L, Scheen A, Paquot N, Piette J, Legrand-Poels S (2013) Unsaturated fatty acids prevent activation of NLRP3 inflammasome in human monocytes/macrophages. J Lipid Res 54:2998–3008PubMedPubMedCentralCrossRefGoogle Scholar
  262. Li Y, Innocentin S, Withers DR, Roberts NA, Gallagher AR, Grigorieva EF, Wilhelm C, Veldhoen M (2011a) Exogenous stimuli maintain intraepithelial lymphocytes via aryl hydrocarbon receptor activation. Cell 147:629–640PubMedCrossRefGoogle Scholar
  263. Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY, Gao B (2011b) AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 13:376–388PubMedPubMedCentralCrossRefGoogle Scholar
  264. Li S, Sullivan NL, Rouphael N, Yu T, Banton S, Maddur MS, McCausland M, Chiu C, Canniff J, Dubey S, Liu K (2017) Metabolic phenotypes of response to vaccination in humans. Cell 169:862–877PubMedCrossRefGoogle Scholar
  265. Lin Y, Tang Y, Wang F (2016) The protective effect of HIF-1α in t lymphocytes on cardiac damage in diabetic mice. Ann Clin Lab Sci 46:32–43PubMedGoogle Scholar
  266. Liu L, Cash TP, Jones RG, Keith B, Thompson CB, Simon MC (2006) Hypoxia-induced energy stress regulates mRNA translation and cell growth. Mol Cell 21:521–531PubMedPubMedCentralCrossRefGoogle Scholar
  267. Liu J, Divoux A, Sun J, Zhang J, Clément K, Glickman JN, Sukhova GK, Wolters PJ, Du J, Gorgun CZ, Doria A (2009) Genetic deficiency and pharmacological stabilization of mast cells reduce diet-induced obesity and diabetes in mice. Nat Med 15:940–945PubMedPubMedCentralCrossRefGoogle Scholar
  268. Liu T, Li J, Liu Y, Xiao N, Suo H, Xie K, Yang C, Wu C (2012) Short-chain fatty acids suppress lipopolysaccharide-induced production of nitric oxide and proinflammatory cytokines through inhibition of NF-κB pathway in RAW264.7 cells. Inflammation 35:1676–1684PubMedCrossRefGoogle Scholar
  269. Liu G, Bi Y, Xue L, Zhang Y, Yang H, Chen X, Lu Y, Zhang Z, Liu H, Wang X, Wang R (2015) Dendritic cell SIRT1–HIF1α axis programs the differentiation of CD4+ T cells through IL-12 and TGF-β1. Proc Natl Acad Sci USA 112:E957–E965PubMedPubMedCentralCrossRefGoogle Scholar
  270. Lizcano JM, Göransson O, Toth R, Deak M, Morrice NA, Boudeau J, Hawley SA, Udd L, Mäkelä TP, Hardie DG, Alessi DR (2004) LKB1 is a master kinase that activates 13 kinases of the AMPK subfamily, including MARK/PAR-1. EMBO J 23:833–843PubMedPubMedCentralCrossRefGoogle Scholar
  271. Lochner M, Berod L, Sparwasser T (2015) Fatty acid metabolism in the regulation of T cell function. Trends Immunol 36:81–91PubMedCrossRefGoogle Scholar
  272. Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J (2005) Rheb binds and regulates the mTOR kinase. Curr Biol 15:702–713PubMedCrossRefGoogle Scholar
  273. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI (1998) Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394:897–901PubMedCrossRefGoogle Scholar
  274. Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M, Stoddard J (2014) Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat Immunol 15:88–97PubMedCrossRefGoogle Scholar
  275. Luo J, Manning BD, Cantley LC (2003) Targeting the PI3K-Akt pathway in human cancer: rationale and promise. Cancer Cell 4:257–262PubMedCrossRefGoogle Scholar
  276. MacDonald PE, Joseph JW, Rorsman P (2005) Glucose-sensing mechanisms in pancreatic β-cells. Philos Trans R Soc Lond B Biol Sci 360:2211–2225PubMedPubMedCentralCrossRefGoogle Scholar
  277. Macintyre AN, Finlay D, Preston G, Sinclair LV, Waugh CM, Tamas P, Feijoo C, Okkenhaug K, Cantrell DA (2011) Protein kinase B controls transcriptional programs that direct cytotoxic T cell fate but is dispensable for T cell metabolism. Immunity 34:224–236PubMedPubMedCentralCrossRefGoogle Scholar
  278. Macintyre AN, Gerriets VA, Nichols AG, Michalek RD, Rudolph MC, Deoliveira D, Anderson SM, Abel ED, Chen BJ, Hale LP, Rathmell JC (2014) The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab 20:61–72PubMedPubMedCentralCrossRefGoogle Scholar
  279. MacIver NJ, Blagih J, Saucillo DC, Tonelli L, Griss T, Rathmell JC, Jones RG (2011) The liver kinase B1 is a central regulator of T cell development, activation, and metabolism. J Immunol 187:4187–4198PubMedPubMedCentralCrossRefGoogle Scholar
  280. MacIver NJ, Michalek RD, Rathmell JC (2013) Metabolic regulation of T lymphocytes. Annu Rev Immunol 31:259–283PubMedPubMedCentralCrossRefGoogle Scholar
  281. MacMicking J, Xie QW, Nathan C (1997) Nitric oxide and macrophage function. Annu Rev Immunol 15:323–350PubMedCrossRefGoogle Scholar
  282. Maekawa Y, Ishifune C, Tsukumo SI, Hozumi K, Yagita H, Yasutomo K (2015) Notch controls the survival of memory CD4+ T cells by regulating glucose uptake. Nat Med 21:55–61PubMedCrossRefGoogle Scholar
  283. Manning BD, Cantley LC (2007) AKT/PKB signaling: navigating downstream. Cell 129:1261–1274PubMedPubMedCentralCrossRefGoogle Scholar
  284. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444PubMedCrossRefGoogle Scholar
  285. Marçais A, Viel S, Grau M, Henry T, Marvel J, Walzer T (2013) Regulation of mouse NK cell development and function by cytokines. Front Immunol 4:450PubMedPubMedCentralCrossRefGoogle Scholar
  286. Marçais A, Cherfils-Vicini J, Viant C, Degouve S, Viel S, Fenis A, Rabilloud J, Mayol K, Tavares A, Bienvenu J, Gangloff YG (2014) The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat Immunol 15:749–757PubMedPubMedCentralCrossRefGoogle Scholar
  287. Mariathasan S, Newton K, Monack DM, Vucic D, French DM, Lee WP, Roose-Girma M, Erickson S, Dixit VM (2004) Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430:213–218PubMedCrossRefGoogle Scholar
  288. Mariathasan S, Weiss DS, Newton K, McBride J, O’rourke K, Roose-Girma M, Lee WP, Weinrauch Y, Monack DM, Dixit VM (2006) Cryopyrin activates the inflammasome in response to toxins and ATP. Nature 440:228–232PubMedCrossRefGoogle Scholar
  289. Marsin AS, Bouzin C, Bertrand L, Hue L (2002) The stimulation of glycolysis by hypoxia in activated monocytes is mediated by AMP-activated protein kinase and inducible 6-phosphofructo-2-kinase. J Biol Chem 277:30778–30783PubMedCrossRefGoogle Scholar
  290. Martinez FO, Gordon S (2014) The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 6:13PubMedPubMedCentralCrossRefGoogle Scholar
  291. Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-β. Mol Cell 10:417–426PubMedCrossRefGoogle Scholar
  292. Maslowski KM, Mackay CR (2011) Diet, gut microbiota and immune responses. Nat Immunol 12:5–9PubMedCrossRefGoogle Scholar
  293. Masters SL, Dunne A, Subramanian SL, Hull RL, Tannahill GM, Sharp FA, Becker C, Franchi L, Yoshihara E, Chen Z, Mullooly N (2010) Activation of the NLRP3 inflammasome by islet amyloid polypeptide provides a mechanism for enhanced IL-1β in type 2 diabetes. Nat Immunol 11:897–904PubMedPubMedCentralCrossRefGoogle Scholar
  294. Masui R, Sasaki M, Funaki Y, Ogasawara N, Mizuno M, Iida A, Izawa S, Kondo Y, Ito Y, Tamura Y, Yanamoto K (2013) G protein-coupled receptor 43 moderates gut inflammation through cytokine regulation from mononuclear cells. Inflamm Bowel Dis 19:2848–2856PubMedCrossRefGoogle Scholar
  295. Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399:271–275PubMedCrossRefGoogle Scholar
  296. Mayne CG, Williams CB (2013) Induced and natural regulatory T cells in the development of inflammatory bowel disease. Inflamm Bowel Dis 19:1772–1788PubMedPubMedCentralCrossRefGoogle Scholar
  297. McCarthy JJ, Esser KA (2010) Anabolic and catabolic pathways regulating skeletal muscle mass. Curr Opin Clin Nutr Metab Care 13:230PubMedPubMedCentralCrossRefGoogle Scholar
  298. McNamee EN, Johnson DK, Homann D, Clambey ET (2013) Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function. Immunol Res 55:58–70PubMedPubMedCentralCrossRefGoogle Scholar
  299. Medzhitov R, Janeway C (2000) Innate immune recognition: mechanisms and pathways. Immunol Rev 173:89–97PubMedCrossRefGoogle Scholar
  300. Mendler AN, Hu B, Prinz PU, Kreutz M, Gottfried E, Noessner E (2012) Tumor lactic acidosis suppresses CTL function by inhibition of p38 and JNK/c-Jun activation. Int J Cancer 131:633–640PubMedCrossRefGoogle Scholar
  301. Meydani SN, Barklund MP, Liu S, Meydani M, Miller RA, Cannon JG, Morrow FD, Rocklin R, Blumberg JB (1990) Vitamin E supplementation enhances cell-mediated immunity in healthy elderly subjects. Am J Clin Nutr 52:557–563PubMedCrossRefGoogle Scholar
  302. Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA (2010) An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol 185:3190–3198PubMedPubMedCentralCrossRefGoogle Scholar
  303. Michalek RD, Rathmell JC (2010) The metabolic life and times of a T-cell. Immunol Rev 236:190–202PubMedPubMedCentralCrossRefGoogle Scholar
  304. Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ, Mason EF, Sullivan SA, Nichols AG, Rathmell JC (2011a) Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 186:3299–3303PubMedPubMedCentralCrossRefGoogle Scholar
  305. Michalek RD, Gerriets VA, Nichols AG, Inoue M, Kazmin D, Chang CY, Dwyer MA, Nelson ER, Pollizzi KN, Ilkayeva O, Giguere V (2011b) Estrogen-related receptor-α is a metabolic regulator of effector T-cell activation and differentiation. Proc Natl Acad Sci USA 108:18348–18353PubMedPubMedCentralCrossRefGoogle Scholar
  306. Michelini RH, Doedens AL, Goldrath AW, Hedrick SM (2013) Differentiation of CD8 memory T cells depends on Foxo1. J Exp Med 210(6):1189–1200. Scholar
  307. Mills CD, Kincaid K, Alt JM, Heilman MJ, Hill AM (2000) M-1/M-2 macrophages and the Th1/Th2 paradigm. J Immunol 164:6166–6173PubMedCrossRefGoogle Scholar
  308. Mills EL, Kelly B, Logan A, Costa AS, Varma M, Bryant CE, Tourlomousis P, Däbritz JH, Gottlieb E, Latorre I, Corr SC (2016) Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167:457–470PubMedPubMedCentralCrossRefGoogle Scholar
  309. Misawa T, Takahama M, Kozaki T, Lee H, Zou J, Saitoh T, Akira S (2013) Microtubule-driven spatial arrangement of mitochondria promotes activation of the NLRP3 inflammasome. Nat Immunol 14:454–460PubMedCrossRefGoogle Scholar
  310. Mogensen TH (2009) Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev 22:240–273PubMedPubMedCentralCrossRefGoogle Scholar
  311. Mok CC, Lau CS (2003) Pathogenesis of systemic lupus erythematosus. J Clin Pathol 56:481–490PubMedPubMedCentralCrossRefGoogle Scholar
  312. Momcilovic M, Hong SP, Carlson M (2006) Mammalian TAK1 activates Snf1 protein kinase in yeast and phosphorylates AMP-activated protein kinase in vitro. J Biol Chem 281:25336–25343PubMedCrossRefGoogle Scholar
  313. Mora JR, Iwata M, Von Andrian UH (2008) Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol 8:685–698PubMedPubMedCentralCrossRefGoogle Scholar
  314. Moretta L, Moretta A (2004) Unravelling natural killer cell function: triggering and inhibitory human NK receptors. EMBO J 23(2):255–259PubMedCrossRefGoogle Scholar
  315. Morris SM (2007) Arginine metabolism: boundaries of our knowledge. J Nutr 137:1602S–1609SPubMedCrossRefGoogle Scholar
  316. Mortha A, Chudnovskiy A, Hashimoto D, Bogunovic M, Spencer SP, Belkaid Y, Merad M (2014) Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343:1249288PubMedPubMedCentralCrossRefGoogle Scholar
  317. Mosmann TR, Coffman RL (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145–173PubMedCrossRefGoogle Scholar
  318. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL (1986) Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 136:2348–2357PubMedGoogle Scholar
  319. Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8:958–969PubMedPubMedCentralCrossRefGoogle Scholar
  320. Mottaghi A, Ebrahimof S, Angoorani P, Saboor-Yaraghi AA (2014) Vitamin A supplementation reduces IL-17 and RORc gene expression in atherosclerotic patients. Scand J Immunol 80:151–157PubMedCrossRefGoogle Scholar
  321. Moussaieff A, Rouleau M, Kitsberg D, Cohen M, Levy G, Barasch D, Nemirovski A, Shen-Orr S, Laevsky I, Amit M, Bomze D (2015) Glycolysis-mediated changes in acetyl-CoA and histone acetylation control the early differentiation of embryonic stem cells. Cell Metab 21:392–402PubMedCrossRefGoogle Scholar
  322. Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317:256–260PubMedCrossRefGoogle Scholar
  323. Mukhopadhyay D, Mukherjee S, Roy S, Dalton JE, Kundu S, Sarkar A, Das NK, Kaye PM, Chatterjee M (2015) M2 polarization of monocytes-macrophages is a hallmark of Indian post kala-azar dermal leishmaniasis. PLoS Negl Trop Dis 9:e0004145PubMedPubMedCentralCrossRefGoogle Scholar
  324. Munn DH, Sharma MD, Lee JR, Jhaver KG, Johnson TS, Keskin DB, Marshall B, Chandler P, Antonia SJ, Burgess R, Slingluff CL (2002) Potential regulatory function of human dendritic cells expressing indoleamine 2, 3-dioxygenase. Science 297:1867–1870PubMedCrossRefGoogle Scholar
  325. Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, Mellor AL (2005) GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2, 3-dioxygenase. Immunity 22:633–642PubMedCrossRefGoogle Scholar
  326. Murphy MP, Siegel RM (2013) Mitochondrial ROS fire up T cell activation. Immunity 38:201–202PubMedCrossRefGoogle Scholar
  327. Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, Hamilton JA, Ivashkiv LB, Lawrence T, Locati M (2014) Macrophage activation and polarization: nomenclature and experimental guidelines. Immunity 41:14–20PubMedPubMedCentralCrossRefGoogle Scholar
  328. Nakahama T, Hanieh H, Nguyen NT, Chinen I, Ripley B, Millrine D, Lee S, Nyati KK, Dubey PK, Chowdhury K, Kawahara Y (2013) Aryl hydrocarbon receptor-mediated induction of the microRNA-132/212 cluster promotes interleukin-17-producing T-helper cell differentiation. Proc Natl Acad Sci USA 110:11964–11969PubMedPubMedCentralCrossRefGoogle Scholar
  329. Nakaya M, Xiao Y, Zhou X, Chang JH, Chang M, Cheng X, Blonska M, Lin X, Sun SC (2014) Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40:692–705PubMedPubMedCentralCrossRefGoogle Scholar
  330. Navarro F, Bacurau AV, Vanzelli A, Meneguello-Coutinho M, Uchida MC, Moraes MR, Almeida SS, Wasinski F, Barros CC, Würtele M, Araújo RC (2010) Changes in glucose and glutamine lymphocyte metabolisms induced by type I interferon α. Mediators Inflamm.
  331. Netea MG, Simon A, van de Veerdonk F, Kullberg BJ, Van der Meer JW, Joosten LA (2010) IL-1β processing in host defense: beyond the inflammasomes. PLoS Pathog 6:e1000661PubMedPubMedCentralCrossRefGoogle Scholar
  332. Newsholme P, Newsholme EA (1989) Rates of utilization of glucose, glutamine and oleate and formation of end-products by mouse peritoneal macrophages in culture. Biochem J 261:211–218PubMedPubMedCentralCrossRefGoogle Scholar
  333. Newsholme P, Curi R, Gordon S, Newsholme EA (1986) Metabolism of glucose, glutamine, long-chain fatty acids and ketone bodies by murine macrophages. Biochem J 239:121–125PubMedPubMedCentralCrossRefGoogle Scholar
  334. Niccoli T, Partridge L (2012) Ageing as a risk factor for disease. Curr Biol 22:R741–R752PubMedCrossRefGoogle Scholar
  335. Nicklin P, Bergman P, Zhang B, Triantafellow E, Wang H, Nyfeler B, Yang H, Hild M, Kung C, Wilson C, Myer VE (2009) Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 136:521–534PubMedPubMedCentralCrossRefGoogle Scholar
  336. Nunn AV, Bell J, Barter P (2007) The integration of lipid-sensing and anti-inflammatory effects: how the PPARs play a role in metabolic balance. Nucl Recept 5:1PubMedPubMedCentralCrossRefGoogle Scholar
  337. O’Brien TF, Gorentla BK, Xie D, Srivatsan S, McLeod IX, He YW, Zhong XP (2011) Regulation of T-cell survival and mitochondrial homeostasis by TSC1. Eur J Immunol 41:3361–3370PubMedPubMedCentralCrossRefGoogle Scholar
  338. O’Sullivan D, van der Windt GJ, Huang SC, Curtis JD, Chang CH, Buck MD, Qiu J, Smith AM, Lam WY, DiPlato LM, Hsu FF (2014) Memory CD8+ T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41:75–88PubMedPubMedCentralCrossRefGoogle Scholar
  339. Odegaard JI, Chawla A (2011) Alternative macrophage activation and metabolism. Annu Rev Pathol Mech Dis 6:275–297CrossRefGoogle Scholar
  340. Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG (2000) Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel–Lindau protein. Nat Cell Biol 2:423–427PubMedCrossRefGoogle Scholar
  341. Okkenhaug K, Ali K, Vanhaesebroeck B (2007) Antigen receptor signalling: a distinctive role for the p110δ isoform of PI3K. Trends Immunol 28:80–87PubMedPubMedCentralCrossRefGoogle Scholar
  342. O’Neill LA (2014) Glycolytic reprogramming by TLRs in dendritic cells. Nat Immunol 15:314–315PubMedCrossRefGoogle Scholar
  343. O’Neill LA, Hardie DG (2013) Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493:346–355PubMedCrossRefGoogle Scholar
  344. Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, Schumacher T, Jestaedt L, Schrenk D, Weller M, Jugold M (2011) An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature 478:197–203PubMedCrossRefGoogle Scholar
  345. O’Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66:1500–1508PubMedPubMedCentralCrossRefGoogle Scholar
  346. Oren R, Farnham AE, Saito K, Milofsky E, Karnovsky ML (1963) Metabolic patterns in three types of phagocytizing cells. J Cell Biol 17:487–501PubMedPubMedCentralCrossRefGoogle Scholar
  347. O’Sullivan D, Pearce EL (2015) Targeting T cell metabolism for therapy. Trends Immunol 36:71–80PubMedPubMedCentralCrossRefGoogle Scholar
  348. Ouyang W, Beckett O, Flavell RA, Li MO (2009) An essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance. Immunity 30:358–371PubMedPubMedCentralCrossRefGoogle Scholar
  349. Pai CC, Kearsey SE (2017) A critical balance: dNTPs and the maintenance of genome stability. Genes 8:57PubMedCentralCrossRefGoogle Scholar
  350. Palazon A, Goldrath AW, Nizet V, Johnson RS (2014) HIF transcription factors, inflammation, and immunity. Immunity 41:518–528PubMedPubMedCentralCrossRefGoogle Scholar
  351. Paludan C, Schmid D, Landthaler M, Vockerodt M, Kube D, Tuschl T, Münz C (2005) Endogenous MHC class II processing of a viral nuclear antigen after autophagy. Science 307:593–596PubMedCrossRefGoogle Scholar
  352. Park J, Kim M, Kang SG, Jannasch AH, Cooper B, Patterson J, Kim CH (2015) Short-chain fatty acids induce both effector and regulatory T cells by suppression of histone deacetylases and regulation of the mTOR–S6K pathway. Mucosal Immunol 8:80–93PubMedCrossRefGoogle Scholar
  353. Parry RV, Chemnitz JM, Frauwirth KA, Lanfranco AR, Braunstein I, Kobayashi SV, Linsley PS, Thompson CB, Riley JL (2005) CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 25:9543–9553PubMedPubMedCentralCrossRefGoogle Scholar
  354. Patsoukis N, Brown J, Petkova V, Liu F, Li L, Boussiotis VA (2012) Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci Signal 5:ra46PubMedPubMedCentralCrossRefGoogle Scholar
  355. Patsoukis N, Bardhan K, Chatterjee P, Sari D, Liu B, Bell LN, Karoly ED, Freeman GJ, Petkova V, Seth P, Li L (2015) PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat Commun 6:6692PubMedPubMedCentralCrossRefGoogle Scholar
  356. Pauly M, Daussin F, Burelle Y, Li T, Godin R, Fauconnier J, Koechlin-Ramonatxo C, Hugon G, Lacampagne A, Coisy-Quivy M, Liang F (2012) AMPK activation stimulates autophagy and ameliorates muscular dystrophy in the mdx mouse diaphragm. Am J Pathol 181:583–592PubMedCrossRefGoogle Scholar
  357. Pearce EJ, Everts B (2015) Dendritic cell metabolism. Nat Rev Immunol 15:18–29PubMedPubMedCentralCrossRefGoogle Scholar
  358. Pearce EL, Pearce EJ (2013) Metabolic pathways in immune cell activation and quiescence. Immunity 38:633–643PubMedPubMedCentralCrossRefGoogle Scholar
  359. Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang LS, Jones RG, Choi Y (2009) Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460:103–107PubMedPubMedCentralCrossRefGoogle Scholar
  360. Pearce EL, Poffenberger MC, Chang CH, Jones RG (2013) Fueling immunity: insights into metabolism and lymphocyte function. Science 342:1242454PubMedPubMedCentralCrossRefGoogle Scholar
  361. Peng YJ, Nanduri J, Khan SA, Yuan G, Wang N, Kinsman B, Vaddi DR, Kumar GK, Garcia JA, Semenza GL, Prabhakar NR (2011) Hypoxia-inducible factor 2α (HIF-2α) heterozygous-null mice exhibit exaggerated carotid body sensitivity to hypoxia, breathing instability, and hypertension. Proc Natl Acad Sci USA 108:3065–3070PubMedPubMedCentralCrossRefGoogle Scholar
  362. Peters NC, Egen JG, Secundino N, Debrabant A, Kimblin N, Kamhawi S, Lawyer P, Fay MP, Germain RN, Sacks D (2008) In vivo imaging reveals an essential role for neutrophils in leishmaniasis transmitted by sand flies. Science 321:970–974PubMedPubMedCentralCrossRefGoogle Scholar
  363. Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, Guertin DA, Madden KL, Carpenter AE, Finck BN, Sabatini DM (2011) mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146:408–420PubMedPubMedCentralCrossRefGoogle Scholar
  364. Peyssonnaux C, Datta V, Cramer T, Doedens A, Theodorakis EA, Gallo RL, Hurtado-Ziola N, Nizet V, Johnson RS (2005) HIF-1α expression regulates the bactericidal capacity of phagocytes. J Clin Invest 115:1806–1815PubMedPubMedCentralCrossRefGoogle Scholar
  365. Phong B, Avery L, Menk AV, Delgoffe GM, Kane LP (2017) Cutting edge: murine mast cells rapidly modulate metabolic pathways essential for distinct effector functions. J Immunol 198:640–644PubMedCrossRefGoogle Scholar
  366. Piemonti L, Monti P, Sironi M, Fraticelli P, Leone BE, Dal Cin E, Allavena P, Di Carlo V (2000) Vitamin D3 affects differentiation, maturation, and function of human monocyte-derived dendritic cells. J Immunol 164:4443–4451PubMedCrossRefGoogle Scholar
  367. Porstmann T, Santos CR, Griffiths B, Cully M, Wu M, Leevers S, Griffiths JR, Chung YL, Schulze A (2008) SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 8:224–236PubMedPubMedCentralCrossRefGoogle Scholar
  368. Pot Kreis C (2012) Aryl hydrocarbon receptor controls regulatory CD4+ T cell function. Swiss Med Weekly 142:w13592Google Scholar
  369. Powell JD, Delgoffe GM (2010) The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity 33:301–311PubMedPubMedCentralCrossRefGoogle Scholar
  370. Powell JD, Lerner CG, Schwartz RH (1999) Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation. J Immunol 162:2775–2784PubMedGoogle Scholar
  371. Pua HH, Dzhagalov I, Chuck M, Mizushima N, He YW (2007) A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp Med 204:25–31PubMedPubMedCentralCrossRefGoogle Scholar
  372. Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Dong H, Accili D, Spiegelman BM (2003) Insulin-regulated hepatic gluconeogenesis through FOXO1–PGC-1α interaction. Nature 423:550–555PubMedCrossRefGoogle Scholar
  373. Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, Caccamo M, Oukka M, Weiner HL (2008) Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature 453:65–71PubMedCrossRefGoogle Scholar
  374. Rajamäki K, Lappalainen J, Öörni K, Välimäki E, Matikainen S, Kovanen PT, Eklund KK (2010) Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One 5:e11765PubMedPubMedCentralCrossRefGoogle Scholar
  375. Ramsay G, Cantrell D (2015) Environmental and metabolic sensors that control T cell biology. Front Immunol 6:99PubMedPubMedCentralCrossRefGoogle Scholar
  376. Rathmell JC, Elstrom RL, Cinalli RM, Thompson CB (2003) Activated Akt promotes increased resting T cell size, CD28-independent T cell growth, and development of autoimmunity and lymphoma. Eur J Immunol 33:2223–2232PubMedCrossRefGoogle Scholar
  377. Raught B, Gingras AC, Sonenberg N (2001) The target of rapamycin (TOR) proteins. Proc Natl Acad Sci USA 98:7037–7044PubMedPubMedCentralCrossRefGoogle Scholar
  378. Ravnskjaer K, Frigerio F, Boergesen M, Nielsen T, Maechler P, Mandrup S (2010) PPARδ is a fatty acid sensor that enhances mitochondrial oxidation in insulin-secreting cells and protects against fatty acid-induced dysfunction. J Lipid Res 51:1370–1379PubMedPubMedCentralCrossRefGoogle Scholar
  379. Reiling JH, Hafen E (2004) The hypoxia-induced paralogs Scylla and Charybdis inhibit growth by down-regulating S6K activity upstream of TSC in Drosophila. Genes Dev 18:2879–2892PubMedPubMedCentralCrossRefGoogle Scholar
  380. Reimer T, Brcic M, Schweizer M, Jungi TW (2008) Poly (I: C) and LPS induce distinct IRF3 and NF-kappaB signaling during type-I IFN and TNF responses in human macrophages. J Leukoc Biol 83:1249–1257PubMedCrossRefGoogle Scholar
  381. Riese MJ, Grewal J, Das J, Zou T, Patil V, Chakraborty AK, Koretzky GA (2011) Decreased diacylglycerol metabolism enhances ERK activation and augments CD8+ T cell functional responses. J Biol Chem 286:5254–5265PubMedCrossRefGoogle Scholar
  382. Rinella ME, Sanyal AJ (2016) Management of NAFLD: a stage-based approach. Nat Rev Gastroenterol Hepatol 13:196–205PubMedCrossRefGoogle Scholar
  383. Rius J, Guma M, Schachtrup C, Akassoglou K, Zinkernagel AS, Nizet V, Johnson RS, Haddad GG, Karin M (2008) NF-κB links innate immunity to the hypoxic response through transcriptional regulation of HIF-1α. Nature 453:807–811PubMedPubMedCentralCrossRefGoogle Scholar
  384. Roos D, Loos JA (1973a) Effect of phytohaemagglutinin on the carbohydrate metabolism of human blood lymphocytes after inhibition of the oxidative phosphorylation. Exp Cell Res 77:121–126PubMedCrossRefGoogle Scholar
  385. Roos D, Loos JA (1973b) Changes in the carbohydrate metabolism of mitogenically stimulated human peripheral lymphocytes: II. Relative importance of glycolysis and oxidative phosphorylation on phytohaemagglutinin stimulation. Exp Cell Res 77:127–135PubMedCrossRefGoogle Scholar
  386. Rutter GA, da Silva XG, Leclerc I (2003) Roles of 5′-AMP-activated protein kinase (AMPK) in mammalian glucose homoeostasis. Biochem J 375:1–6PubMedPubMedCentralCrossRefGoogle Scholar
  387. Ryan HE, Lo J, Johnson RS (1998) HIF-1α is required for solid tumor formation and embryonic vascularization. EMBO J 17:3005–3015PubMedPubMedCentralCrossRefGoogle Scholar
  388. Sakai J, Duncan EA, Rawson RB, Hua X, Brown MS, Goldstein JL (1996) Sterol-regulated release of SREBP-2 from cell membranes requires two sequential cleavages, one within a transmembrane segment. Cell 85:1037–1046PubMedCrossRefGoogle Scholar
  389. Sakamoto T, Seiki M (2009) Mint3 enhances the activity of hypoxia-inducible factor-1 (HIF-1) in macrophages by suppressing the activity of factor inhibiting HIF-1. J Biol Chem 284:30350–30359PubMedPubMedCentralCrossRefGoogle Scholar
  390. Sallusto F, Lenig D, Förster R, Lipp M, Lanzavecchia A (1999) Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401:708–712PubMedCrossRefGoogle Scholar
  391. Salminen A, Hyttinen JM, Kaarniranta K (2011) AMP-activated protein kinase inhibits NF-κB signaling and inflammation: impact on healthspan and lifespan. J Mol Med 89:667–676PubMedPubMedCentralCrossRefGoogle Scholar
  392. Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, Sabatini DM (2008) The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 320:1496–1501PubMedPubMedCentralCrossRefGoogle Scholar
  393. Sancak Y, Bar-Peled L, Zoncu R, Markhard AL, Nada S, Sabatini DM (2010) Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids. Cell 141:290–303PubMedPubMedCentralCrossRefGoogle Scholar
  394. Satoh-Takayama N, Vosshenrich CA, Lesjean-Pottier S, Sawa S, Lochner M, Rattis F, Mention JJ, Thiam K, Cerf-Bensussan N, Mandelboim O, Eberl G (2008) Microbial flora drives interleukin 22 production in intestinal NKp46+ cells that provide innate mucosal immune defense. Immunity 29:958–970PubMedCrossRefGoogle Scholar
  395. Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, Knight ZA, Cobb BS, Cantrell D, O’Connor E, Shokat KM (2008) T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci USA 105:7797–7802PubMedPubMedCentralCrossRefGoogle Scholar
  396. Sayed BA, Christy A, Quirion MR, Brown MA (2008) The master switch: the role of masT cells in autoimmunity and tolerance. Annu Rev Immunol 26:705–739PubMedCrossRefGoogle Scholar
  397. Scharping NE, Menk AV, Moreci RS, Whetstone RD, Dadey RE, Watkins SC, Ferris RL, Delgoffe GM (2016) The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45:374–388PubMedPubMedCentralCrossRefGoogle Scholar
  398. Scheu S, Stetson DB, Reinhardt RL, Leber JH, Mohrs M, Locksley RM (2006) Activation of the integrated stress response during T helper cell differentiation. Nat Immunol 7:644–651PubMedCrossRefGoogle Scholar
  399. Schmelzle T, Hall MN (2000) TOR, a central controller of cell growth. Cell 103:253–262PubMedCrossRefGoogle Scholar
  400. Schuhmacher M, Kohlhuber F, Hölzel M, Kaiser C, Burtscher H, Jarsch M, Bornkamm GW, Laux G, Polack A, Weidle UH, Eick D (2001) The transcriptional program of a human B cell line in response to Myc. Nucleic Acids Res 29:397–406PubMedPubMedCentralCrossRefGoogle Scholar
  401. Schwartz RH (2003) T cell anergy. Annu Rev Immunol 21:305–334PubMedCrossRefGoogle Scholar
  402. Seidel UJ, Schlegel P, Lang P (2013) Natural killer cell mediated antibody-dependent cellular cytotoxicity in tumor immunotherapy with therapeutic antibodies. Front Immunol 4:76PubMedPubMedCentralCrossRefGoogle Scholar
  403. Semenza GL, Wang GL (1992) A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 12:5447–5454PubMedPubMedCentralCrossRefGoogle Scholar
  404. Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman DA, Wang CR, Schumacker PT, Licht JD, Perlman H, Bryce PJ (2013) Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38:225–236PubMedPubMedCentralCrossRefGoogle Scholar
  405. Sengupta S, Peterson TR, Sabatini DM (2010) Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell 40:310–322PubMedPubMedCentralCrossRefGoogle Scholar
  406. Shang L, Chen S, Du F, Li S, Zhao L, Wang X (2011) Nutrient starvation elicits an acute autophagic response mediated by Ulk1 dephosphorylation and its subsequent dissociation from AMPK. Proc Natl Acad Sci USA 108:4788–4793PubMedPubMedCentralCrossRefGoogle Scholar
  407. Shaw RJ, Cantley LC (2006) Ras, PI(3)K and mTOR signalling controls tumour cell growth. Nature 441:424–430PubMedCrossRefGoogle Scholar
  408. Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, Cantley LC (2004) The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA 101:3329–3335PubMedPubMedCentralCrossRefGoogle Scholar
  409. Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, DePinho RA, Montminy M, Cantley LC (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310:1642–1646PubMedPubMedCentralCrossRefGoogle Scholar
  410. Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H (2011) HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208:1367–1376PubMedPubMedCentralCrossRefGoogle Scholar
  411. Shimobayashi M, Hall MN (2016) Multiple amino acid sensing inputs to mTORC1. Cell Res 26:7–20PubMedCrossRefGoogle Scholar
  412. Shirai T, Nazarewicz RR, Wallis BB, Yanes RE, Watanabe R, Hilhorst M, Tian L, Harrison DG, Giacomini JC, Assimes TL, Goronzy JJ (2016) The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. J Exp Med 213:337–354PubMedPubMedCentralCrossRefGoogle Scholar
  413. Sica A, Schioppa T, Mantovani A, Allavena P (2006) Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 42:717–727PubMedCrossRefGoogle Scholar
  414. Sims JE, Smith DE (2010) The IL-1 family: regulators of immunity. Nat Rev Immunol 10:89–102PubMedCrossRefGoogle Scholar
  415. Sinclair LV, Rolf J, Emslie E, Shi YB, Taylor PM, Cantrell DA (2013) Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat Immunol 14:500–508PubMedPubMedCentralCrossRefGoogle Scholar
  416. Singh NP, Singh UP, Singh B, Price RL, Nagarkatti M, Nagarkatti PS (2011) Activation of aryl hydrocarbon receptor (AhR) leads to reciprocal epigenetic regulation of FoxP3 and IL-17 expression and amelioration of experimental colitis. PLoS One 6:e23522PubMedPubMedCentralCrossRefGoogle Scholar
  417. Smith EM, Finn SG, Tee AR, Browne GJ, Proud CG (2005) The tuberous sclerosis protein TSC2 is not required for the regulation of the mammalian target of rapamycin by amino acids and certain cellular stresses. J Biol Chem 280:18717–18727PubMedCrossRefGoogle Scholar
  418. Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly-y M, Glickman JN, Garrett WS (2013) The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341:569–573PubMedCrossRefGoogle Scholar
  419. Smith-Garvin JE, Koretzky GA, Jordan MS (2009) T cell activation. Annu Rev Immunol 27:591–619PubMedPubMedCentralCrossRefGoogle Scholar
  420. Song MY, Wang J, Lee Y, Lee J, Kwon KS, Bae EJ, Park BH (2016) Enhanced M2 macrophage polarization in high n-3 polyunsaturated fatty acid transgenic mice fed a high-fat diet. Mol Nutr Food Res 60:2481–2492PubMedCrossRefGoogle Scholar
  421. Sood R, Porter AC, Olsen D, Cavener DR, Wek RC (2000) A mammalian homologue of GCN2 protein kinase important for translational control by phosphorylation of eukaryotic initiation factor-2α. Genetics 154:787–801PubMedPubMedCentralGoogle Scholar
  422. Stone KD, Prussin C, Metcalfe DD (2010) IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 125:S73–S80PubMedPubMedCentralCrossRefGoogle Scholar
  423. Straub RH, Cutolo M, Buttgereit F, Pongratz G (2010) Energy regulation and neuroendocrine–immune control in chronic inflammatory diseases. J Internal Med 267:543–560PubMedCrossRefGoogle Scholar
  424. Sukumar M, Roychoudhuri R, Restifo NP (2015) Nutrient competition: a new axis of tumor immunosuppression. Cell 162:1206–1208PubMedCrossRefGoogle Scholar
  425. Sun X, Kanwar JR, Leung E, Lehnert K, Wang D, Krissansen GW (2001) Gene transfer of antisense hypoxia inducible factor-1 α enhances the therapeutic efficacy of cancer immunotherapy. Gene Therapy 8:638PubMedCrossRefGoogle Scholar
  426. Sun Y, Connors KE, Yang DQ (2007) AICAR induces phosphorylation of AMPK in an ATM-dependent, LKB1-independent manner. Mol Cell Biochem 306:239–245PubMedCrossRefGoogle Scholar
  427. Sun K, Kusminski CM, Scherer PE (2011a) Adipose tissue remodeling and obesity. J Clin Invest 121:2094–2101PubMedPubMedCentralCrossRefGoogle Scholar
  428. Sun Q, Chen X, Ma J, Peng H, Wang F, Zha X, Wang Y, Jing Y, Yang H, Chen R, Chang L (2011b) Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci USA 108:4129–4134PubMedPubMedCentralCrossRefGoogle Scholar
  429. Sundrud MS, Koralov SB, Feuerer M, Calado DP, Kozhaya AE, Rhule-Smith A, Lefebvre RE, Unutmaz D, Mazitschek R, Waldner H, Whitman M (2009) Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science 324:1334–1338PubMedPubMedCentralCrossRefGoogle Scholar
  430. Széles L, Töröcsik D, Nagy L (2007) PPARγ in immunity and inflammation: cell types and diseases. BBA Mol Cell Biol Lipids 1771:1014–1030CrossRefGoogle Scholar
  431. Tabor CW, Tabor H (1984) Polyamines. Annu Rev Biochem 53:749–790PubMedCrossRefGoogle Scholar
  432. Taildeman J, Pérez-Novo CA, Rottiers I, Ferdinande L, Waeytens A, De Colvenaer V, Bachert C, Demetter P, Waelput W, Braet K, Cuvelier CA (2009) Human mast cells express leptin and leptin receptors. Histochem Cell Biol 131:703–711PubMedCrossRefGoogle Scholar
  433. Tamás P, Hawley SA, Clarke RG, Mustard KJ, Green K, Hardie DG, Cantrell DA (2006) Regulation of the energy sensor AMP-activated protein kinase by antigen receptor and Ca2+ in T lymphocytes. J Exp Med 203:1665–1670PubMedPubMedCentralCrossRefGoogle Scholar
  434. Tamás P, Macintyre A, Finlay D, Clarke R, Feijoo-Carnero C, Ashworth A, Cantrell D (2010) LKB1 is essential for the proliferation of T-cell progenitors and mature peripheral T cells. Eur J Immunol 40:242–253PubMedPubMedCentralCrossRefGoogle Scholar
  435. Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, Frezza C, Bernard NJ, Kelly B, Foley NH, Zheng L (2013) Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496:238–242PubMedPubMedCentralCrossRefGoogle Scholar
  436. Tennessen JM, Baker KD, Lam G, Evans J, Thummel CS (2011) The Drosophila estrogen-related receptor directs a metabolic switch that supports developmental growth. Cell Metab 13:139–148PubMedPubMedCentralCrossRefGoogle Scholar
  437. Tontonoz P, Nagy L, Alvarez JG, Thomazy VA, Evans RM (1998) PPARγ promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93:241–252PubMedCrossRefGoogle Scholar
  438. Topham NJ, Hewitt EW (2009) Natural killer cell cytotoxicity: how do they pull the trigger? Immunology 128:7–15PubMedPubMedCentralCrossRefGoogle Scholar
  439. Traut TW (1994) Physiological concentrations of purines and pyrimidines. Mol Cell Biochem 140(1):1–22PubMedCrossRefGoogle Scholar
  440. Tzameli I, Fang H, Ollero M, Shi H, Hamm JK, Kievit P, Hollenberg AN, Flier JS (2004) Regulated production of a peroxisome proliferator-activated receptor-γ ligand during an early phase of adipocyte differentiation in 3T3-L1 adipocytes. J Biol Chem 279:36093–36102PubMedCrossRefGoogle Scholar
  441. Uematsu S, Akira S (2007) Toll-like receptors and type I interferons. J Biol Chem 282:15319–15323PubMedCrossRefGoogle Scholar
  442. Uyttenhove C, Pilotte L, Théate I, Stroobant V, Colau D, Parmentier N, Boon T, Van den Eynde BJ (2003) Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2, 3-dioxygenase. Nat Med 9:1269–1274PubMedCrossRefGoogle Scholar
  443. Valledor AF, Hsu LC, Ogawa S, Sawka-Verhelle D, Karin M, Glass CK (2004) Activation of liver X receptors and retinoid X receptors prevents bacterial-induced macrophage apoptosis. Proc Natl Acad Sci USA 101:17813–17818PubMedPubMedCentralCrossRefGoogle Scholar
  444. van der Windt GJ, Everts B, Chang CH, Curtis JD, Freitas TC, Amiel E, Pearce EJ, Pearce EL (2012) Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36:68–78PubMedCrossRefGoogle Scholar
  445. Van Dyken SJ, Locksley RM (2013) Interleukin-4- and interleukin-13-mediated alternatively activated macrophages: roles in homeostasis and disease. Annu Rev Immunol 31:317–343PubMedPubMedCentralCrossRefGoogle Scholar
  446. Van Kessel KP, Bestebroer J, van Strijp JA (2014) Neutrophil-mediated phagocytosis of Staphylococcus aureus. Front Immunol 5:467PubMedPubMedCentralGoogle Scholar
  447. van Loosdregt J, Fleskens V, Tiemessen MM, Mokry M, van Boxtel R, Meerding J, Pals CE, Kurek D, Baert MR, Delemarre EM, Gröne A (2013) Canonical Wnt signaling negatively modulates regulatory T cell function. Immunity 39:298–310PubMedCrossRefGoogle Scholar
  448. Van Raam BJ, Sluiter W, De Wit E, Roos D, Verhoeven AJ, Kuijpers TW (2008) Mitochondrial membrane potential in human neutrophils is maintained by complex III activity in the absence of supercomplex organisation. PLoS One 3:e2013PubMedPubMedCentralCrossRefGoogle Scholar
  449. Van YH, Lee WH, Ortiz S, Lee MH, Qin HJ, Liu CP (2009) All-trans retinoic acid inhibits type 1 diabetes by T regulatory (Treg)-dependent suppression of interferon-γ-producing T-cells without affecting Th17 cells. Diabetes 58:146–155PubMedPubMedCentralCrossRefGoogle Scholar
  450. Vander Heiden MG, Cantley LC, Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324:1029–1033PubMedPubMedCentralCrossRefGoogle Scholar
  451. Vander Heiden MG, Lunt SY, Dayton TL, Fiske BP, Israelsen WJ, Mattaini KR, Vokes NI, Stephanopoulos G, Cantley LC, Metallo CM, Locasale JW (2011) Metabolic pathway alterations that support cell proliferation. Cold Spring Harbor Symp Quant Biol 76:325–334PubMedCrossRefGoogle Scholar
  452. Vattem KM, Wek RC (2004) Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Proc Natl Acad Sci USA 101:11269–11274PubMedPubMedCentralCrossRefGoogle Scholar
  453. Veldhoen M, Hirota K, Christensen J, O’Garra A, Stockinger B (2009) Natural agonists for aryl hydrocarbon receptor in culture medium are essential for optimal differentiation of Th17 T cells. J Exp Med 206:43–49PubMedPubMedCentralCrossRefGoogle Scholar
  454. Viel S, Marçais A, Guimaraes FS, Loftus R, Rabilloud J, Grau M, Degouve S, Djebali S, Sanlaville A, Charrier E, Bienvenu J (2016) TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway. Sci Signal 9:ra19PubMedCrossRefGoogle Scholar
  455. Vinolo MA, Rodrigues HG, Nachbar RT, Curi R (2011) Regulation of inflammation by short chain fatty acids. Nutrients 3:858–876PubMedPubMedCentralCrossRefGoogle Scholar
  456. Vita AJ, Terry RB, Hubert HB, Fries JF (1998) Aging, health risks, and cumulative disability. N Engl J Med 338:1035–1041PubMedCrossRefGoogle Scholar
  457. Walmsley SR, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, Sobolewski A, Condliffe AM, Cowburn AS, Johnson N, Chilvers ER (2005) Hypoxia-induced neutrophil survival is mediated by HIF-1α-dependent NF-κB activity. J Exp Med 201:105–115PubMedPubMedCentralCrossRefGoogle Scholar
  458. Walsh CM, Fruman DA (2014) Too much of a good thing: immunodeficiency due to hyperactive PI3K signaling. J Clin Invest 124:3688–3690PubMedPubMedCentralCrossRefGoogle Scholar
  459. Wang R, Green DR (2012) Metabolic checkpoints in activated T cells. Nat Immunol 13:907–915PubMedCrossRefGoogle Scholar
  460. Wang X, Proud CG (2006) The mTOR pathway in the control of protein synthesis. Physiology 21:362–369PubMedCrossRefGoogle Scholar
  461. Wang X, Sato R, Brown MS, Hua X, Goldstein JL (1994) SREBP-1, a membrane-bound transcription factor released by sterol-regulated proteolysis. Cell 77:53–62PubMedCrossRefGoogle Scholar
  462. Wang GL, Jiang BH, Rue EA, Semenza GL (1995) Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension. Proc Natl Acad Sci USA 92:5510–5514PubMedPubMedCentralCrossRefGoogle Scholar
  463. Wang R, Dillon CP, Shi LZ, Milasta S, Carter R, Finkelstein D, McCormick LL, Fitzgerald P, Chi H, Munger J, Green DR (2011) The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35:871–882PubMedPubMedCentralCrossRefGoogle Scholar
  464. Wang S, Tsun ZY, Wolfson RL, Shen K, Wyant GA, Plovanich ME, Yuan ED, Jones TD, Chantranupong L, Comb W, Wang T (2015) Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 347:188–194PubMedPubMedCentralCrossRefGoogle Scholar
  465. Ward PS, Thompson CB (2012) Metabolic reprogramming: a cancer hallmark even Warburg did not anticipate. Cancer Cell 21:297–308PubMedPubMedCentralCrossRefGoogle Scholar
  466. Warden SM, Richardson C, O’Donnell J, Stapleton D, Witters LA (2001) Post-translational modifications of the β-1 subunit of AMP-activated protein kinase affect enzyme activity and cellular localization. Biochem J 354:275–283PubMedPubMedCentralCrossRefGoogle Scholar
  467. Watson E, Yilmaz LS, Walhout AJ (2015) Understanding metabolic regulation at a systems level: metabolite sensing, mathematical predictions, and model organisms. Annu Rev Genet 49:553–575PubMedCrossRefGoogle Scholar
  468. Waugh C, Sinclair L, Finlay D, Bayascas JR, Cantrell D (2009) Phosphoinositide (3,4,5)-triphosphate binding to phosphoinositide-dependent kinase 1 regulates a protein kinase B/Akt signaling threshold that dictates T-cell migration, not proliferation. Mol Cell Biol 29:5952–5962PubMedPubMedCentralCrossRefGoogle Scholar
  469. Wek RC, Jiang HY, Anthony TG (2006) Coping with stress: eIF2 kinases and translational control. Biochem Soc Trans 34:7–11PubMedCrossRefGoogle Scholar
  470. Wen H, Gris D, Lei Y, Jha S, Zhang L, Huang MT, Brickey WJ, Ting JP (2011) Fatty acid-induced NLRP3-ASC inflammasome activation interferes with insulin signaling. Nat Immunol 12:408–415PubMedPubMedCentralCrossRefGoogle Scholar
  471. Wen H, Ting JP, O’Neill LA (2012) A role for the NLRP3 inflammasome in metabolic diseases—did Warburg miss inflammation? Nat Immunol 13:352–357PubMedPubMedCentralCrossRefGoogle Scholar
  472. Wenes M, Shang M, Di Matteo M, Goveia J, Martín-Pérez R, Serneels J, Prenen H, Ghesquière B, Carmeliet P, Mazzone M (2016) Macrophage metabolism controls tumor blood vessel morphogenesis and metastasis. Cell Metab 24:701–715PubMedCrossRefGoogle Scholar
  473. Weng NP, Akbar AN, Goronzy J (2009) CD28− T cells: their role in the age-associated decline of immune function. Trends Immunol 30:306–312PubMedPubMedCentralCrossRefGoogle Scholar
  474. Wensveen FM, Jelenčić V, Valentić S, Šestan M, Wensveen TT, Theurich S, Glasner A, Mendrila D, Štimac D, Wunderlich FT, Brüning JC (2015) NK cells link obesity-induced adipose stress to inflammation and insulin resistance. Nat Immunol 16:376–385PubMedCrossRefGoogle Scholar
  475. West AP, Brodsky IE, Rahner C, Woo DK, Erdjument-Bromage H, Tempst P, Walsh MC, Choi Y, Shadel GS, Ghosh S (2011) TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature 472:476–480PubMedPubMedCentralCrossRefGoogle Scholar
  476. Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, Glasauer A, Dufour E, Mutlu GM, Budigner GS, Chandel NS (2014) Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. elife 3Google Scholar
  477. Wherry EJ (2011) T cell exhaustion. Nat Immunol 12:492–499PubMedCrossRefGoogle Scholar
  478. Wherry JC, Schreiber RD, Unanue ER (1991) Regulation of gamma interferon production by natural killer cells in SCID mice: roles of tumor necrosis factor and bacterial stimuli. Infect Immun 59:1709–1715PubMedPubMedCentralGoogle Scholar
  479. Wieman HL, Wofford JA, Rathmell JC (2007) Cytokine stimulation promotes glucose uptake via phosphatidylinositol-3 kinase/Akt regulation of Glut1 activity and trafficking. Mol Biol Cell 18:1437–1446PubMedPubMedCentralCrossRefGoogle Scholar
  480. Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY, Pfeiffer HK, Nissim I, Daikhin E, Yudkoff M, McMahon SB, Thompson CB (2008) Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 105:18782–18787PubMedPubMedCentralCrossRefGoogle Scholar
  481. Wofford JA, Wieman HL, Jacobs SR, Zhao Y, Rathmell JC (2008) IL-7 promotes Glut1 trafficking and glucose uptake via STAT5-mediated activation of Akt to support T-cell survival. Blood 111:2101–2111PubMedPubMedCentralCrossRefGoogle Scholar
  482. Wojtaszewski JF, Jørgensen SB, Hellsten Y, Hardie DG, Richter EA (2002) Glycogen-dependent effects of 5-aminoimidazole-4-carboxamide (AICA)-riboside on AMP-activated protein kinase and glycogen synthase activities in rat skeletal muscle. Diabetes 51:284–292PubMedCrossRefGoogle Scholar
  483. Woo SR, Corrales L, Gajewski TF (2015) Innate immune recognition of cancer. Annu Rev Immunol 33:445–474PubMedCrossRefGoogle Scholar
  484. Woods A, Vertommen D, Neumann D, Türk R, Bayliss J, Schlattner U, Wallimann T, Carling D, Rider MH (2003) Identification of phosphorylation sites in AMP-activated protein kinase (AMPK) for upstream AMPK kinases and study of their roles by site-directed mutagenesis. J Biol Chem 278:28434–28442PubMedCrossRefGoogle Scholar
  485. Wu X, Huang M (2008) Dif1 controls subcellular localization of ribonucleotide reductase by mediating nuclear import of the R2 subunit. Mol Cell Biol 28:7156–7167PubMedPubMedCentralCrossRefGoogle Scholar
  486. Wu Q, Liu Y, Chen C, Ikenoue T, Qiao Y, Li CS, Li W, Guan KL, Liu Y, Zheng P (2011) The tuberous sclerosis complex–mammalian target of rapamycin pathway maintains the quiescence and survival of naive T cells. J Immunol 187:1106–1112PubMedPubMedCentralCrossRefGoogle Scholar
  487. Wullschleger S, Loewith R, Hall MN (2006) TOR signaling in growth and metabolism. Cell 124:471–484PubMedCrossRefGoogle Scholar
  488. Wumesh KC, Satpathy AT, Rapaport AS, Briseño CG, Wu X, Albring JC, Russler-Germain EV, Kretzer NM, Durai V, Persaud SP, Edelson BT (2014) L-Myc expression by dendritic cells is required for optimal T-cell priming. Nature 507:243–247PubMedCentralCrossRefGoogle Scholar
  489. Xie X, Zhang D, Zhao B, Lu MK, You M, Condorelli G, Wang CY, Guan KL (2011) IκB kinase ε and TANK-binding kinase 1 activate AKT by direct phosphorylation. Proc Natl Acad Sci USA 108:6474–6479PubMedPubMedCentralCrossRefGoogle Scholar
  490. Xiao B, Sanders MJ, Underwood E, Heath R, Mayer FV, Carmena D, Jing C, Walker PA, Eccleston JF, Haire LF, Saiu P (2011) Structure of mammalian AMPK and its regulation by ADP. Nature 472:230PubMedPubMedCentralCrossRefGoogle Scholar
  491. Xu J, Wagoner G, Douglas JC, Drew PD (2009) Liver X receptor agonist regulation of Th17 lymphocyte function in autoimmunity. J Leukoc Biol 86:401–409PubMedPubMedCentralCrossRefGoogle Scholar
  492. Yang XY, Wang LH, Chen T, Hodge DR, Resau JH, DaSilva L, Farrar WL (2000) Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor γ (PPARγ) agonists PPARγ co-association with transcription factor NFAT. J Biol Chem 275:4541–4544PubMedCrossRefGoogle Scholar
  493. Yang K, Neale G, Green DR, He W, Chi H (2011) The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat Immunol 12:888–897PubMedPubMedCentralCrossRefGoogle Scholar
  494. Yao R, Zhang Z, An X, Bucci B, Perlstein DL, Stubbe J, Huang M (2003) Subcellular localization of yeast ribonucleotide reductase regulated by the DNA replication and damage checkpoint pathways. Proc Natl Acad Sci USA 100:6628–6633PubMedPubMedCentralCrossRefGoogle Scholar
  495. Zhao E, Maj T, Kryczek I, Li W, Wu K, Zhao L, Wei S, Crespo J, Wan S, Vatan L, Szeliga W (2015) Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat Immunol 17:95–103PubMedPubMedCentralCrossRefGoogle Scholar
  496. Zheng Y, Collins SL, Lutz MA, Allen AN, Kole TP, Zarek PE, Powell JD (2007) A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J Immunol 178:2163–2170PubMedCrossRefGoogle Scholar
  497. Zheng Y, Delgoffe GM, Meyer CF, Chan W, Powell JD (2009) Anergic T cells are metabolically anergic. J Immunol 183:6095–6101PubMedPubMedCentralCrossRefGoogle Scholar
  498. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174PubMedPubMedCentralCrossRefGoogle Scholar
  499. Zhou X, Clister TL, Lowry PR, Seldin MM, Wong GW, Zhang J (2015a) Dynamic visualization of mTORC1 activity in living cells. Cell Rep 10:1767–1777CrossRefGoogle Scholar
  500. Zhou Y, Yu X, Chen H, Sjöberg S, Roux J, Zhang L, Ivoulsou AH, Bensaid F, Liu CL, Liu J, Tordjman J (2015b) Leptin deficiency shifts mast cells toward anti-inflammatory actions and protects mice from obesity and diabetes by polarizing M2 macrophages. Cell Metab 22:1045–1058PubMedPubMedCentralCrossRefGoogle Scholar
  501. Zhu J, Yamane H, Paul WE (2009) Differentiation of effector CD4 T cell populations. Annu Rev Immunol 28:445–489CrossRefGoogle Scholar
  502. Zhu L, Yang T, Li L, Sun L, Hou Y, Hu X, Zhang L, Tian H, Zhao Q, Peng J, Zhang H (2014) TSC1 controls macrophage polarization to prevent inflammatory disease. Nat Commun 5:4696PubMedCrossRefGoogle Scholar
  503. Zindy F, Eischen CM, Randle DH, Kamijo T, Cleveland JL, Sherr CJ, Roussel MF (1998) Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev 12:2424–2433PubMedPubMedCentralCrossRefGoogle Scholar
  504. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21–35PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Prashant Chauhan
    • 1
  • Arup Sarkar
    • 2
  • Bhaskar Saha
    • 2
  1. 1.National Centre for Cell SciencePuneIndia
  2. 2.Trident Academy of Creative TechnologyBhubaneswarIndia

Personalised recommendations