Abstract
The immune system is a central determinant of organismal health. Functional immune responses require quiescent immune cells to rapidly grow, proliferate, and acquire effector functions when they sense infectious agents or other insults. Specialized metabolic programs are critical regulators of immune responses, and alterations in immune metabolism can cause immunological disorders. There has thus been growing interest in understanding how metabolic processes control immune cell functions under normal and pathophysiological conditions. In this chapter, we summarize how metabolic programs are tuned and what the physiological consequences of metabolic reprogramming are as they relate to immune cell homeostasis, differentiation, and function.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Abbas AK, Benoist C, Bluestone JA, Campbell DJ, Ghosh S, Hori S, Jiang S, Kuchroo VK, Mathis D, Roncarolo MG, Rudensky A, Sakaguchi S, Shevach EM, Vignali DA, Ziegler SF (2013) Regulatory T cells: recommendations to simplify the nomenclature. Nat Immunol 14(4):307–308. doi:10.1038/ni.2554
Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, Evans RM (2013) PPARgamma signaling and metabolism: the good, the bad and the future. Nat Med 19(5):557–566. doi:10.1038/nm.3159
Ai D, Jiang H, Westerterp M, Murphy AJ, Wang M, Ganda A, Abramowicz S, Welch C, Almazan F, Zhu Y, Miller YI, Tall AR (2014) Disruption of mammalian target of rapamycin complex 1 in macrophages decreases chemokine gene expression and atherosclerosis. Circ Res 114(10):1576–1584. doi:10.1161/CIRCRESAHA.114.302313
Akula MK, Shi M, Jiang Z, Foster CE, Miao D, Li AS, Zhang X, Gavin RM, Forde SD, Germain G, Carpenter S, Rosadini CV, Gritsman K, Chae JJ, Hampton R, Silverman N, Gravallese EM, Kagan JC, Fitzgerald KA, Kastner DL, Golenbock DT, Bergo MO, Wang D (2016) Control of the innate immune response by the mevalonate pathway. Nat Immunol 17(8):922–929. doi:10.1038/ni.3487
Amiel E, Everts B, Freitas TC, King IL, Curtis JD, Pearce EL, Pearce EJ (2012) Inhibition of mechanistic target of rapamycin promotes dendritic cell activation and enhances therapeutic autologous vaccination in mice. J Immunol 189(5):2151–2158. doi:10.4049/jimmunol.1103741
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(27):18793–18804. doi:10.1074/jbc.M114.554113
Angeli V, Hammad H, Staels B, Capron M, Lambrecht BN, Trottein F (2003) Peroxisome proliferator-activated receptor gamma inhibits the migration of dendritic cells: consequences for the immune response. J Immunol 170(10):5295–5301
Apostolidis SA, Rodriguez-Rodriguez N, Suarez-Fueyo A, Dioufa N, Ozcan E, Crispin JC, Tsokos MG, Tsokos GC (2016) Phosphatase PP2A is requisite for the function of regulatory T cells. Nat Immunol 17(5):556–564. doi:10.1038/ni.3390
Appel S, Mirakaj V, Bringmann A, Weck MM, Grunebach F, Brossart P (2005) PPAR-gamma agonists inhibit toll-like receptor-mediated activation of dendritic cells via the MAP kinase and NF-kappaB pathways. Blood 106(12):3888–3894. doi:10.1182/blood-2004-12-4709
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(7251):108–112. doi:10.1038/nature08155
Arpaia N, Campbell C, Fan X, Dikiy S, van der Veeken J, deRoos P, Liu H, Cross JR, Pfeffer K, Coffer PJ, Rudensky AY (2013) Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation. Nature 504(7480):451–455. doi:10.1038/nature12726
Arranz A, Doxaki C, Vergadi E, Martinez de la Torre Y, Vaporidi K, Lagoudaki ED, Ieronymaki E, Androulidaki A, Venihaki M, Margioris AN, Stathopoulos EN, Tsichlis PN, Tsatsanis C (2012) Akt1 and Akt2 protein kinases differentially contribute to macrophage polarization. Proc Natl Acad Sci U.S.A. 109(24):9517–9522. doi:10.1073/pnas.1119038109
Artis D, Spits H (2015) The biology of innate lymphoid cells. Nature 517(7534):293–301. doi:10.1038/nature14189
Atkuri KR, Herzenberg LA, Herzenberg LA (2005) Culturing at atmospheric oxygen levels impacts lymphocyte function. Proc Natl Acad Sci U.S.A. 102(10):3756–3759. doi:10.1073/pnas.0409910102
Atkuri KR, Herzenberg LA, Niemi AK, Cowan T, Herzenberg LA (2007) Importance of culturing primary lymphocytes at physiological oxygen levels. Proc Natl Acad Sci U.S.A. 104(11):4547–4552. doi:10.1073/pnas.0611732104
Baginska J, Viry E, Paggetti J, Medves S, Berchem G, Moussay E, Janji B (2013) The critical role of the tumor microenvironment in shaping natural killer cell-mediated anti-tumor immunity. Front Immunol 4:490. doi:10.3389/fimmu.2013.00490
Baixauli F, Acin-Perez R, Villarroya-Beltri C, Mazzeo C, Nunez-Andrade N, Gabande-Rodriguez E, Ledesma MD, Blazquez A, Martin MA, Falcon-Perez JM, Redondo JM, Enriquez JA, Mittelbrunn M (2015) Mitochondrial respiration controls lysosomal function during inflammatory T cell responses. Cell Metab 22(3):485–498. doi:10.1016/j.cmet.2015.07.020
Ballesteros-Tato A, Leon B, Graf BA, Moquin A, Adams PS, Lund FE, Randall TD (2012) Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36(5):847–856. doi:10.1016/j.immuni.2012.02.012
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(10):2756–2764. doi:10.1002/eji.201343448
Bar-Peled L, Chantranupong L, Cherniack AD, Chen WW, Ottina KA, Grabiner BC, Spear ED, Carter SL, Meyerson M, Sabatini DM (2013) A tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science 340(6136):1100–1106. doi:10.1126/science.1232044
Battaglia M, Stabilini A, Migliavacca B, Horejs-Hoeck J, Kaupper T, Roncarolo MG (2006) Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol (Baltimore, Md: 1950) 177(12):8338–8347
Bauer DE, Hatzivassiliou G, Zhao F, Andreadis C, Thompson CB (2005) ATP citrate lyase is an important component of cell growth and transformation. Oncogene 24(41):6314–6322. doi:10.1038/sj.onc.1208773
Beier UH, Angelin A, Akimova T, Wang L, Liu Y, Xiao H, Koike MA, Hancock SA, Bhatti TR, Han R, Jiao J, Veasey SC, Sims CA, Baur JA, Wallace DC, Hancock WW (2015) Essential role of mitochondrial energy metabolism in Foxp3(+) T-regulatory cell function and allograft survival. FASEB J: Off Publ Fed Am Soc Exp Biol 29(6):2315–2326. doi:10.1096/fj.14-268409
Belikov AV, Schraven B, Simeoni L (2015) T cells and reactive oxygen species. J Biomed Sci 22:85. doi:10.1186/s12929-015-0194-3
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-1alpha. Eur J Immunol 38(9):2412–2418. doi:10.1002/eji.200838318
Benhamron S, Tirosh B (2011) Direct activation of mTOR in B lymphocytes confers impairment in B-cell maturation andloss of marginal zone B cells. Eur J Immunol 41(8):2390–2396. doi:10.1002/eji.201041336
Bennett CL, Christie J, Ramsdell F, Brunkow ME, Ferguson PJ, Whitesell L, Kelly TE, Saulsbury FT, Chance PF, Ochs HD (2001) The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet 27(1):20–21. doi:10.1038/83713
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(1):97–111. doi:10.1016/j.cell.2008.04.052
Bentley J, Itchayanan D, Barnes K, McIntosh E, Tang X, Downes CP, Holman GD, Whetton AD, Owen-Lynch PJ, Baldwin SA (2003) Interleukin-3-mediated cell survival signals include phosphatidylinositol 3-kinase-dependent translocation of the glucose transporter GLUT1 to the cell surface. J Biol Chem 278(41):39337–39348. doi:10.1074/jbc.M305689200
Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S, Harmrolfs K, Sandouk A, Hesse C, Castro CN, Bahre H, Tschirner SK, Gorinski N, Gohmert M, Mayer CT, Huehn J, Ponimaskin E, Abraham WR, Muller R, Lochner M, Sparwasser T (2014) De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med 20(11):1327–1333. doi:10.1038/nm.3704
Bhandari T, Olson J, Johnson RS, Nizet V (2013) HIF-1alpha influences myeloid cell antigen presentation and response to subcutaneous OVA vaccination. J Mol Med 91(10):1199–1205. doi:10.1007/s00109-013-1052-y
Blagih J, Coulombe F, Vincent EE, Dupuy F, Galicia-Vazquez G, Yurchenko E, Raissi TC, van der Windt GJ, 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(1):41–54. doi:10.1016/j.immuni.2014.12.030
Blanc M, Hsieh WY, Robertson KA, Kropp KA, Forster T, Shui G, Lacaze P, Watterson S, Griffiths SJ, Spann NJ, Meljon A, Talbot S, Krishnan K, Covey DF, Wenk MR, Craigon M, Ruzsics Z, Haas J, Angulo A, Griffiths WJ, Glass CK, Wang Y, Ghazal P (2013) The transcription factor STAT-1 couples macrophage synthesis of 25-hydroxycholesterol to the interferon antiviral response. Immunity 38(1):106–118. doi:10.1016/j.immuni.2012.11.004
Blanc M, Hsieh WY, Robertson KA, Watterson S, Shui G, Lacaze P, Khondoker M, Dickinson P, Sing G, Rodriguez-Martin S, Phelan P, Forster T, Strobl B, Muller M, Riemersma R, Osborne T, Wenk MR, Angulo A, Ghazal P (2011) Host defense against viral infection involves interferon mediated down-regulation of sterol biosynthesis. PLoS Biol 9(3):e1000598. doi:10.1371/journal.pbio.1000598
Blasius AL, Arnold CN, Georgel P, Rutschmann S, Xia Y, Lin P, Ross C, Li X, Smart NG, Beutler B (2010) Slc15a4, AP-3, and Hermansky-Pudlak syndrome proteins are required for Toll-like receptor signaling in plasmacytoid dendritic cells. Proc Natl Acad Sci U.S.A. 107(46):19973–19978. doi:10.1073/pnas.1014051107
Blouin CC, Page EL, Soucy GM, Richard DE (2004) Hypoxic gene activation by lipopolysaccharide in macrophages: implication of hypoxia-inducible factor 1alpha. Blood 103(3):1124–1130. doi:10.1182/blood-2003-07-2427
Boor PP, Metselaar HJ, Mancham S, van der Laan LJ, Kwekkeboom J (2013) Rapamycin has suppressive and stimulatory effects on human plasmacytoid dendritic cell functions. Clin Exp Immunol 174(3):389–401. doi:10.1111/cei.12191
Bouhlel MA, Derudas B, Rigamonti E, Dievart R, Brozek J, Haulon S, Zawadzki C, Jude B, Torpier G, Marx N, Staels B, Chinetti-Gbaguidi G (2007) PPARgamma activation primes human monocytes into alternative M2 macrophages with anti-inflammatory properties. Cell Metab 6(2):137–143. doi:10.1016/j.cmet.2007.06.010
Boxer RB, Stairs DB, Dugan KD, Notarfrancesco KL, Portocarrero CP, Keister BA, Belka GK, Cho H, Rathmell JC, Thompson CB, Birnbaum MJ, Chodosh LA (2006) Isoform-specific requirement for Akt1 in the developmental regulation of cellular metabolism during lactation. Cell Metab 4(6):475–490. doi:10.1016/j.cmet.2006.10.011
Brestoff JR, Kim BS, Saenz SA, Stine RR, Monticelli LA, Sonnenberg GF, Thome JJ, Farber DL, Lutfy K, Seale P, Artis D (2015) Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519(7542):242–246. doi:10.1038/nature14115
Bronte V, Zanovello P (2005) Regulation of immune responses by L-arginine metabolism. Nat Rev Immunol 5(8):641–654. doi:10.1038/nri1668
Brown J, Wang H, Suttles J, Graves DT, Martin M (2011) Mammalian target of rapamycin complex 2 (mTORC2) negatively regulates Toll-like receptor 4-mediated inflammatory response via FoxO1. J Biol Chem 286(52):44295–44305. doi:10.1074/jbc.M111.258053
Brunet A, Park J, Tran H, Hu LS, Hemmings BA, Greenberg ME (2001) Protein kinase SGK mediates survival signals by phosphorylating the forkhead transcription factor FKHRL1 (FOXO3a). Mol Cell Biol 21(3):952–965. doi:10.1128/MCB.21.3.952-965.2001
Brunkow ME, Jeffery EW, Hjerrild KA, Paeper B, Clark LB, Yasayko SA, Wilkinson JE, Galas D, Ziegler SF, Ramsdell F (2001) Disruption of a new forkhead/winged-helix protein, scurfin, results in the fatal lymphoproliferative disorder of the scurfy mouse. Nat Genet 27(1):68–73. doi:10.1038/83784
Buck MD, O’Sullivan D, Klein Geltink RI, Curtis JD, Chang CH, Sanin DE, Qiu J, Kretz O, Braas D, van der Windt GJ, Chen Q, Huang SC, O’Neill CM, Edelson BT, Pearce EJ, Sesaki H, Huber TB, Rambold AS, Pearce EL (2016) Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166(1):63–76. doi:10.1016/j.cell.2016.05.035
Buck MD, O’Sullivan D, Pearce EL (2015) T cell metabolism drives immunity. J Exp Med 212(9):1345–1360. doi:10.1084/jem.20151159
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(8):698–704. doi:10.1038/90633
Bukowski JF, Morita CT, Brenner MB (1999) Human gamma delta T cells recognize alkylamines derived from microbes, edible plants, and tea: implications for innate immunity. Immunity 11(1):57–65
Burke B, Tang N, Corke KP, Tazzyman D, Ameri K, Wells M, Lewis CE (2002) Expression of HIF-1alpha by human macrophages: implications for the use of macrophages in hypoxia-regulated cancer gene therapy. J Pathol 196(2):204–212. doi:10.1002/path.1029
Busada JT, Chappell VA, Niedenberger BA, Kaye EP, Keiper BD, Hogarth CA, Geyer CB (2015) Retinoic acid regulates Kit translation during spermatogonial differentiation in the mouse. Dev Biol 397(1):140–149
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(18):3230–3237. doi:10.1182/blood-2013-04-495515
Byles V, Covarrubias AJ, Ben-Sahra I, Lamming DW, Sabatini DM, Manning BD, Horng T (2013) The TSC-mTOR pathway regulates macrophage polarization. Nat Commun 4:2834. doi:10.1038/ncomms3834
Caldwell CC, Kojima H, Lukashev D, Armstrong J, Farber M, Apasov SG, Sitkovsky MV (2001) Differential effects of physiologically relevant hypoxic conditions on T lymphocyte development and effector functions. J Immunol 167(11):6140–6149
Calnan DR, Brunet A (2008) The FoxO code. Oncogene 27(16):2276–2288. doi:10.1038/onc.2008.21
Cao W, Manicassamy S, Tang H, Kasturi SP, Pirani A, Murthy N, Pulendran B (2008) Toll-like receptor-mediated induction of type I interferon in plasmacytoid dendritic cells requires the rapamycin-sensitive PI(3)K-mTOR-p70S6K pathway. Nat Immunol 9(10):1157–1164. doi:10.1038/ni.1645
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(1):99–108. doi:10.1038/cr.2009.141
Carlson CM, Endrizzi BT, Wu J, Ding X, Weinreich MA, Walsh ER, Wani MA, Lingrel JB, Hogquist KA, Jameson SC (2006) Kruppel-like factor 2 regulates thymocyte and T-cell migration. Nature 442(7100):299–302. doi:10.1038/nature04882
Caro-Maldonado A, Wang R, Nichols AG, Kuraoka M, Milasta S, Sun LD, Gavin AL, Abel ED, Kelsoe G, Green DR, Rathmell JC (2014) Metabolic reprogramming is required for antibody production that is suppressed in anergic but exaggerated in chronically BAFF-exposed B cells. J Immunol 192(8):3626–3636. doi:10.4049/jimmunol.1302062
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(2):1037–1044. doi:10.4049/jimmunol.0903586
Carroll KC, Viollet B, Suttles J (2013) AMPKalpha1 deficiency amplifies proinflammatory myeloid APC activity and CD40 signaling. J Leukoc Biol 94(6):1113–1121. doi:10.1189/jlb.0313157
Castellano E, Downward J (2011) RAS interaction with PI3K: more than just another effector pathway. Genes Cancer 2(3):261–274. doi:10.1177/1947601911408079
Chakrabarti R, Engleman EG (1991) Interrelationships between mevalonate metabolism and the mitogenic signaling pathway in T lymphocyte proliferation. J Biol Chem 266(19):12216–12222
Cham CM, Gajewski TF (2005) Glucose availability regulates IFN-gamma production and p70S6 kinase activation in CD8+ effector T cells. J Immunol 174(8):4670–4677
Chang CH, Curtis JD, Maggi LB Jr, Faubert B, Villarino AV, O’Sullivan D, Huang SC, van der Windt GJ, Blagih J, Qiu J, Weber JD, Pearce EJ, Jones RG, Pearce EL (2013a) Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153(6):1239–1251. doi:10.1016/j.cell.2013.05.016
Chang HC, Sehra S, Goswami R, Yao W, Yu Q, Stritesky GL, Jabeen R, McKinley C, Ahyi AN, Han L, Nguyen ET, Robertson MJ, Perumal NB, Tepper RS, Nutt SL, Kaplan MH (2010) The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol 11(6):527–534. doi:10.1038/ni.1867
Chang J, Burkett PR, Borges CM, Kuchroo VK, Turka LA, Chang CH (2013b) MyD88 is essential to sustain mTOR activation necessary to promote T helper 17 cell proliferation by linking IL-1 and IL-23 signaling. Proc Natl Acad Sci U.S.A. 110(6):2270–2275. doi:10.1073/pnas.1206048110
Chang JT, Palanivel VR, Kinjyo I, Schambach F, Intlekofer AM, Banerjee A, Longworth SA, Vinup KE, Mrass P, Oliaro J, Killeen N, Orange JS, Russell SM, Weninger W, Reiner SL (2007) Asymmetric T lymphocyte division in the initiation of adaptive immune responses. Science 315(5819):1687–1691. doi:10.1126/science.1139393
Chatila TA, Blaeser F, Ho N, Lederman HM, Voulgaropoulos C, Helms C, Bowcock AM (2000) JM2, encoding a fork head-related protein, is mutated in X-linked autoimmunity-allergic disregulation syndrome. J Clin Invest 106(12):R75–R81. doi:10.1172/JCI11679
Chi H (2012) Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol 12(5):325–338. doi:10.1038/nri3198
Chinen T, Kannan AK, Levine AG, Fan X, Klein U, Zheng Y, Gasteiger G, Feng Y, Fontenot JD, Rudensky AY (2016) An essential role for the IL-2 receptor in Treg cell function. Nat Immunol. doi:10.1038/ni.3540
Choi YS, Gullicksrud JA, Xing S, Zeng Z, Shan Q, Li F, Love PE, Peng W, Xue HH, Crotty S (2015) LEF-1 and TCF-1 orchestrate T(FH) differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6. Nat Immunol 16(9):980–990. doi:10.1038/ni.3226
Chou C, Pinto AK, Curtis JD, Persaud SP, Cella M, Lin CC, Edelson BT, Allen PM, Colonna M, Pearce EL, Diamond MS, Egawa T (2014) c-Myc-induced transcription factor AP4 is required for host protection mediated by CD8+ T cells. Nat Immunol 15(9):884–893. doi:10.1038/ni.2943
Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE, Benoist C, Mathis D (2012) PPAR-gamma is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486(7404):549–553. doi:10.1038/nature11132
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 U.S.A. 109(41):E2784–E2793. doi:10.1073/pnas.1202366109
Clark RB, Bishop-Bailey D, Estrada-Hernandez T, Hla T, Puddington L, Padula SJ (2000) The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates inhibition of helper T cell responses. J Immunol 164(3):1364–1371
Clever D, Roychoudhuri R, Constantinides MG, Askenase MH, Sukumar M, Klebanoff CA, Eil RL, Hickman HD, Yu Z, Pan JH, Palmer DC, Phan AT, Goulding J, Gattinoni L, Goldrath AW, Belkaid Y, Restifo NP (2016) Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche. Cell 166(5):1117–1131. e1114. doi:10.1016/j.cell.2016.07.032
Cobbold SP, Adams E, Farquhar CA, Nolan KF, Howie D, Lui KO, Fairchild PJ, Mellor AL, Ron D, Waldmann H (2009) Infectious tolerance via the consumption of essential amino acids and mTOR signaling. Proc Natl Acad Sci U.S.A. 106(29):12055–12060. doi:10.1073/pnas.0903919106
Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F (2007) A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med 204(8):1757–1764. doi:10.1084/jem.20070590
Cooper MA, Elliott JM, Keyel PA, Yang L, Carrero JA, Yokoyama WM (2009) Cytokine-induced memory-like natural killer cells. Proc Natl Acad Sci U.S.A. 106(6):1915–1919. doi:10.1073/pnas.0813192106
Covarrubias AJ, Aksoylar HI, Horng T (2015) Control of macrophage metabolism and activation by mTOR and Akt signaling. Semin Immunol 27(4):286–296. doi:10.1016/j.smim.2015.08.001
Cramer T, Yamanishi Y, Clausen BE, Forster I, Pawlinski R, Mackman N, Haase VH, Jaenisch R, Corr M, Nizet V, Firestein GS, Gerber HP, Ferrara N, Johnson RS (2003) HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 112(5):645–657
Cui G, Qin X, Wu L, Zhang Y, Sheng X, Yu Q, Sheng H, Xi B, Zhang JZ, Zang YQ (2011) Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation. J Clin Invest 121(2):658–670. doi:10.1172/JCI42974
Cui Y, Chen X, Zhang J, Sun X, Liu H, Bai L, Xu C, Liu X (2016) Uhrf1 controls iNKT cell survival and differentiation through the Akt-mTOR Axis. Cell Rep 15(2):256–263. doi:10.1016/j.celrep.2016.03.016
Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P (2007) mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 450(7170):736–740. doi:10.1038/nature06322
Cyster JG, Dang EV, Reboldi A, Yi T (2014) 25-Hydroxycholesterols in innate and adaptive immunity. Nat Rev Immunol 14(11):731–743. doi:10.1038/nri3755
Dang EV, Barbi J, Yang HY, Jinasena D, Yu H, Zheng Y, Bordman Z, Fu J, Kim Y, Yen HR, Luo W, Zeller K, Shimoda L, Topalian SL, Semenza GL, Dang CV, Pardoll DM, Pan F (2011) Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 146(5):772–784. doi:10.1016/j.cell.2011.07.033
de Jong AJ, Kloppenburg M, Toes RE, Ioan-Facsinay A (2014) Fatty acids, lipid mediators, and T-cell function. Front Immunol 5:483. doi:10.3389/fimmu.2014.00483
De Rosa V, Galgani M, Porcellini A, Colamatteo A, Santopaolo M, Zuchegna C, Romano A, De Simone S, Procaccini C, La Rocca C, Carrieri PB, Maniscalco GT, Salvetti M, Buscarinu MC, Franzese A, Mozzillo E, La Cava A, Matarese G (2015) Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat Immunol 16(11):1174–1184. doi:10.1038/ni.3269
De Rosa V, Procaccini C, Cali G, Pirozzi G, Fontana S, Zappacosta S, La Cava A, Matarese G (2007) A key role of leptin in the control of regulatory T cell proliferation. Immunity 26(2):241–255. doi:10.1016/j.immuni.2007.01.011
De Saedeleer CJ, Copetti T, Porporato PE, Verrax J, Feron O, Sonveaux P (2012) Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells. PLoS One 7(10):e46571. doi:10.1371/journal.pone.0046571
De Silva NS, Klein U (2015) Dynamics of B cells in germinal centres. Nat Rev Immunol 15(3):137–148. doi:10.1038/nri3804
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(6):832–844. doi:10.1016/j.immuni.2009.04.014
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(4):295–303. doi:10.1038/ni.2005
Delgoffe GM, Woo SR, Turnis ME, Gravano DM, Guy C, Overacre AE, Bettini ML, Vogel P, Finkelstein D, Bonnevier J, Workman CJ, Vignali DA (2013) Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4a axis. Nature 501(7466):252–256. doi:10.1038/nature12428
Deng Y, Kerdiles Y, Chu J, Yuan S, Wang Y, Chen X, Mao H, Zhang L, Zhang J, Hughes T, Zhang Q, Wang F, Zou X, Liu CG, Freud AG, Li X, Caligiuri MA, Vivier E, Yu J (2015) Transcription factor Foxo1 is a negative regulator of natural killer cell maturation and function. Immunity 42(3):457–470. doi:10.1016/j.immuni.2015.02.006
Depeint F, Bruce WR, Shangari N, Mehta R, O’Brien PJ (2006) Mitochondrial function and toxicity: role of B vitamins on the one-carbon transfer pathways. Chem Biol Interact 163(1–2):113–132. doi:10.1016/j.cbi.2006.05.010
Desreumaux P, Dubuquoy L, Nutten S, Peuchmaur M, Englaro W, Schoonjans K, Derijard B, Desvergne B, Wahli W, Chambon P, Leibowitz MD, Colombel JF, Auwerx J (2001) Attenuation of colon inflammation through activators of the retinoid X receptor (RXR)/peroxisome proliferator-activated receptor gamma (PPARgamma) heterodimer. A basis for new therapeutic strategies. J Exp Med 193(7):827–838
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(11):1173–1182. doi:10.1038/ni.2714
Doege H, Stahl A (2006) Protein-mediated fatty acid uptake: novel insights from in vivo models. Physiology 21:259–268. doi:10.1152/physiol.00014.2006
Donnelly RP, Loftus RM, Keating SE, Liou KT, Biron CA, Gardiner CM, Finlay DK (2014) mTORC1-dependent metabolic reprogramming is a prerequisite for NK cell effector function. J Immunol 193(9):4477–4484. doi:10.4049/jimmunol.1401558
Doughty CA, Bleiman BF, Wagner DJ, Dufort FJ, Mataraza JM, Roberts MF, Chiles TC (2006) Antigen receptor-mediated changes in glucose metabolism in B lymphocytes: role of phosphatidylinositol 3-kinase signaling in the glycolytic control of growth. Blood 107(11):4458–4465. doi:10.1182/blood-2005-12-4788
Dufort FJ, Bleiman BF, Gumina MR, Blair D, Wagner DJ, Roberts MF, Abu-Amer Y, Chiles TC (2007) Cutting edge: IL-4-mediated protection of primary B lymphocytes from apoptosis via Stat6-dependent regulation of glycolytic metabolism. J Immunol 179(8):4953–4957
Dunn SE, Youssef S, Goldstein MJ, Prod’homme T, Weber MS, Zamvil SS, Steinman L (2006) Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin. J Exp Med 203(2):401–412. doi:10.1084/jem.20051129
Ecker J, Liebisch G, Englmaier M, Grandl M, Robenek H, Schmitz G (2010) Induction of fatty acid synthesis is a key requirement for phagocytic differentiation of human monocytes. Proc Natl Acad Sci U.S.A. 107(17):7817–7822. doi:10.1073/pnas.0912059107
Egan DF, Shackelford DB, Mihaylova MM, Gelino S, Kohnz RA, Mair W, Vasquez DS, Joshi A, Gwinn DM, Taylor R, Asara JM, Fitzpatrick J, Dillin A, Viollet B, Kundu M, Hansen M, Shaw RJ (2011) Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 331(6016):456–461. doi:10.1126/science.1196371
Eijkelenboom A, Burgering BM (2013) FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol 14(2):83–97. doi:10.1038/nrm3507
Endo Y, Asou HK, Matsugae N, Hirahara K, Shinoda K, Tumes DJ, Tokuyama H, Yokote K, Nakayama T (2015) Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase, ACC1. Cell Rep 12(6):1042–1055. doi:10.1016/j.celrep.2015.07.014
Everts B, Amiel E, Huang SC, Smith AM, Chang CH, Lam WY, Redmann V, Freitas TC, Blagih J, van der Windt GJ, Artyomov MN, Jones RG, Pearce EL, Pearce EJ (2014) TLR-driven early glycolytic reprogramming via the kinases TBK1-IKKvarepsilon supports the anabolic demands of dendritic cell activation. Nat Immunol 15(4):323–332. doi:10.1038/ni.2833
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(7):1422–1431. doi:10.1182/blood-2012-03-419747
Fan W, Morinaga H, Kim JJ, Bae E, Spann NJ, Heinz S, Glass CK, Olefsky JM (2010) FoxO1 regulates Tlr4 inflammatory pathway signalling in macrophages. EMBO J 29(24):4223–4236. doi:10.1038/emboj.2010.268
Fang C, Yu J, Luo Y, Chen S, Wang W, Zhao C, Sun Z, Wu W, Guo W, Han Z, Hu X, Liao F, Feng X (2015) Tsc1 is a critical regulator of macrophage survival and function. Cell Physiol Biochem 36(4):1406–1418. doi:10.1159/000430306
Faveeuw C, Fougeray S, Angeli V, Fontaine J, Chinetti G, Gosset P, Delerive P, Maliszewski C, Capron M, Staels B, Moser M, Trottein F (2000) Peroxisome proliferator-activated receptor gamma activators inhibit interleukin-12 production in murine dendritic cells. FEBS Lett 486(3):261–266
Feng X, Wang H, Takata H, Day TJ, Willen J, Hu H (2011) Transcription factor Foxp1 exerts essential cell-intrinsic regulation of the quiescence of naive T cells. Nat Immunol 12(6):544–550. doi:10.1038/ni.2034
Fernandez-Marcos PJ, Auwerx J (2011) Regulation of PGC-1alpha, a nodal regulator of mitochondrial biogenesis. Am J Clin Nutr 93(4):884S–8890. doi:10.3945/ajcn.110.001917
Festuccia WT, Pouliot P, Bakan I, Sabatini DM, Laplante M (2014) Myeloid-specific Rictor deletion induces M1 macrophage polarization and potentiates in vivo pro-inflammatory response to lipopolysaccharide. PLoS One 9(4):e95432. doi:10.1371/journal.pone.0095432
Finlay DK (2012) Regulation of glucose metabolism in T cells: new insight into the role of Phosphoinositide 3-kinases. Front Immunol 3:247. doi:10.3389/fimmu.2012.00247
Finlay DK, Rosenzweig E, Sinclair LV, Feijoo-Carnero C, Hukelmann JL, Rolf J, Panteleyev AA, Okkenhaug K, Cantrell DA (2012) PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J Exp Med 209(13):2441–2453. doi:10.1084/jem.20112607
Finlay DK, Sinclair LV, Feijoo C, Waugh CM, Hagenbeek TJ, Spits H, Cantrell DA (2009) Phosphoinositide-dependent kinase 1 controls migration and malignant transformation but not cell growth and proliferation in PTEN-null lymphocytes. J Exp Med 206(11):2441–2454. doi:10.1084/jem.20090219
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(2):275–283. doi:10.1158/0008-5472.can-14-1491
Fontenot JD, Rasmussen JP, Williams LM, Dooley JL, Farr AG, Rudensky AY (2005) Regulatory T cell lineage specification by the forkhead transcription factor foxp3. Immunity 22(3):329–341. doi:10.1016/j.immuni.2005.01.016
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(6):769–777
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(11):7884–7896. doi:10.1074/jbc.M113.522037
Fullerton MD, Galic S, Marcinko K, Sikkema S, Pulinilkunnil T, Chen ZP, O’Neill HM, Ford RJ, Palanivel R, O’Brien M, Hardie DG, Macaulay SL, Schertzer JD, Dyck JR, van Denderen BJ, Kemp BE, Steinberg GR (2013) Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med 19(12):1649–1654. doi:10.1038/nm.3372
Furusawa Y, Obata Y, Fukuda S, Endo TA, Nakato G, Takahashi D, Nakanishi Y, Uetake C, Kato K, Kato T, Takahashi M, Fukuda NN, Murakami S, Miyauchi E, Hino S, Atarashi K, Onawa S, Fujimura Y, Lockett T, Clarke JM, Topping DL, Tomita M, Hori S, Ohara O, Morita T, Koseki H, Kikuchi J, Honda K, Hase K, Ohno H (2013) Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504(7480):446–450. doi:10.1038/nature12721
Galic S, Fullerton MD, Schertzer JD, Sikkema S, Marcinko K, Walkley CR, Izon D, Honeyman J, Chen ZP, van Denderen BJ, Kemp BE, Steinberg GR (2011) Hematopoietic AMPK beta1 reduces mouse adipose tissue macrophage inflammation and insulin resistance in obesity. J Clin Invest 121(12):4903–4915. doi:10.1172/JCI58577
Galvan-Pena S, O’Neill LA (2014) Metabolic reprograming in macrophage polarization. Front Immunol 5:420. doi:10.3389/fimmu.2014.00420
Gan X, Wang J, Su B, Wu D (2011) Evidence for direct activation of mTORC2 kinase activity by phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 286(13):10998–11002. doi:10.1074/jbc.M110.195016
Ganeshan K, Chawla A (2014) Metabolic regulation of immune responses. Annu Rev Immunol 32:609–634. doi:10.1146/annurev-immunol-032713-120236
Ganguly D, Haak S, Sisirak V, Reizis B (2013) The role of dendritic cells in autoimmunity. Nat Rev Immunol 13(8):566–577. doi:10.1038/nri3477
Ganley IG, Lam du H, Wang J, Ding X, Chen S, Jiang X (2009) ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 284(18):12297–12305. doi:10.1074/jbc.M900573200
Gehart H, Kumpf S, Ittner A, Ricci R (2010) MAPK signalling in cellular metabolism: stress or wellness? EMBO Rep 11(11):834–840. doi:10.1038/embor.2010.160
Gerriets VA, Kishton RJ, Nichols AG, Macintyre AN, Inoue M, Ilkayeva O, Winter PS, Liu X, Priyadharshini B, Slawinska ME, Haeberli L, Huck C, Turka LA, Wood KC, Hale LP, Smith PA, Schneider MA, MacIver NJ, Locasale JW, Newgard CB, Shinohara ML, Rathmell JC (2015) Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J Clin Invest 125(1):194–207. doi:10.1172/JCI76012
Giandomenico V, Simonsson M, Gronroos E, Ericsson J (2003) Coactivator-dependent acetylation stabilizes members of the SREBP family of transcription factors. Mol Cell Biol 23(7):2587–2599
Gober HJ, Kistowska M, Angman L, Jeno P, Mori L, De Libero G (2003) Human T cell receptor gammadelta cells recognize endogenous mevalonate metabolites in tumor cells. J Exp Med 197(2):163–168
Gomez-Rodriguez J, Meylan F, Handon R, Hayes ET, Anderson SM, Kirby MR, Siegel RM, Schwartzberg PL (2016) Itk is required for Th9 differentiation via TCR-mediated induction of IL-2 and IRF4. Nat Commun 7:10857. doi:10.1038/ncomms10857
Gomez-Rodriguez J, Wohlfert EA, Handon R, Meylan F, Wu JZ, Anderson SM, Kirby MR, Belkaid Y, Schwartzberg PL (2014) Itk-mediated integration of T cell receptor and cytokine signaling regulates the balance between Th17 and regulatory T cells. J Exp Med 211(3):529–543. doi:10.1084/jem.20131459
Gorentla BK, Wan CK, Zhong XP (2011) Negative regulation of mTOR activation by diacylglycerol kinases. Blood 117(15):4022–4031. doi:10.1182/blood-2010-08-300731
Gorman S, Kuritzky LA, Judge MA, Dixon KM, McGlade JP, Mason RS, Finlay-Jones JJ, Hart PH (2007) Topically applied 1,25-dihydroxyvitamin D3 enhances the suppressive activity of CD4+CD25+ cells in the draining lymph nodes. J Immunol 179(9):6273–6283
Gosset P, Charbonnier AS, Delerive P, Fontaine J, Staels B, Pestel J, Tonnel AB, Trottein F (2001) Peroxisome proliferator-activated receptor gamma activators affect the maturation of human monocyte-derived dendritic cells. Eur J Immunol 31(10):2857–2865
Goswami R, Kaplan MH (2012) Gcn5 is required for PU.1-dependent IL-9 induction in Th9 cells. J Immunol 189(6):3026–3033. doi:10.4049/jimmunol.1201496
Greenwood J, Steinman L, Zamvil SS (2006) Statin therapy and autoimmune disease: from protein prenylation to immunomodulation. Nat Rev Immunol 6(5):358–370. doi:10.1038/nri1839
Gross DN, van den Heuvel AP, Birnbaum MJ (2008) The role of FoxO in the regulation of metabolism. Oncogene 27(16):2320–2336. doi:10.1038/onc.2008.25
Gualdoni GA, Mayer KA, Goschl L, Boucheron N, Ellmeier W, Zlabinger GJ (2016) The AMP analog AICAR modulates the Treg/Th17 axis through enhancement of fatty acid oxidation. FASEB J: Off Publ Fed Am Soc Exp Biol. doi:10.1096/fj.201600522R
Gubbels Bupp MR, Edwards B, Guo C, Wei D, Chen G, Wong B, Masteller E, Peng SL (2009) T cells require Foxo1 to populate the peripheral lymphoid organs. Eur J Immunol 39(11):2991–2999. doi:10.1002/eji.200939427
Gulen MF, Kang Z, Bulek K, Youzhong W, Kim TW, Chen Y, Altuntas CZ, Sass Bak-Jensen K, McGeachy MJ, Do JS, Xiao H, Delgoffe GM, Min B, Powell JD, Tuohy VK, Cua DJ, Li X (2010) The receptor SIGIRR suppresses Th17 cell proliferation via inhibition of the interleukin-1 receptor pathway and mTOR kinase activation. Immunity 32(1):54–66. doi:10.1016/j.immuni.2009.12.003
Guo F, Iclozan C, Suh WK, Anasetti C, Yu XZ (2008) CD28 controls differentiation of regulatory T cells from naive CD4 T cells. J Immunol 181(4):2285–2291
Haas R, Smith J, Rocher-Ros V, Nadkarni S, Montero-Melendez T, D’Acquisto F, Bland EJ, Bombardieri M, Pitzalis C, Perretti M, Marelli-Berg FM, Mauro C (2015) Lactate regulates metabolic and pro-inflammatory circuits in control of T cell migration and effector functions. PLoS Biol 13(7):e1002202. doi:10.1371/journal.pbio.1002202
Hagenbeek TJ, Naspetti M, Malergue F, Garcon F, Nunes JA, Cleutjens KB, Trapman J, Krimpenfort P, Spits H (2004) The loss of PTEN allows TCR alphabeta lineage thymocytes to bypass IL-7 and Pre-TCR-mediated signaling. J Exp Med 200(7):883–894. doi:10.1084/jem.20040495
Haghikia A, Jorg S, Duscha A, Berg J, Manzel A, Waschbisch A, Hammer A, Lee DH, May C, Wilck N, Balogh A, Ostermann AI, Schebb NH, Akkad DA, Grohme DA, Kleinewietfeld M, Kempa S, Thone J, Demir S, Muller DN, Gold R, Linker RA (2015) Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity 43(4):817–829. doi:10.1016/j.immuni.2015.09.007
Haidinger M, Poglitsch M, Geyeregger R, Kasturi S, Zeyda M, Zlabinger GJ, Pulendran B, Horl WH, Saemann MD, Weichhart T (2010) A versatile role of mammalian target of rapamycin in human dendritic cell function and differentiation. J Immunol 185(7):3919–3931. doi:10.4049/jimmunol.1000296
Hamilton KS, Phong B, Corey C, Cheng J, Gorentla B, Zhong X, Shiva S, Kane LP (2014) T cell receptor-dependent activation of mTOR signaling in T cells is mediated by Carma1 and MALT1, but not Bcl10. Sci Signal 7(329):ra55. doi:10.1126/scisignal.2005169
Hard GC (1970) Some biochemical aspects of the immune macrophage. Br J Exp Pathol 51(1):97–105
Harms M, Seale P (2013) Brown and beige fat: development, function and therapeutic potential. Nat Med 19(10):1252–1263. doi:10.1038/nm.3361
Haschemi A, Kosma P, Gille L, Evans CR, Burant CF, Starkl P, Knapp B, Haas R, Schmid JA, Jandl C, Amir S, Lubec G, Park J, Esterbauer H, Bilban M, Brizuela L, Pospisilik JA, Otterbein LE, Wagner O (2012) The sedoheptulose kinase CARKL directs macrophage polarization through control of glucose metabolism. Cell Metab 15(6):813–826. doi:10.1016/j.cmet.2012.04.023
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(44):27879–27887
Hedrick SM, Hess Michelini R, Doedens AL, Goldrath AW, Stone EL (2012) FOXO transcription factors throughout T cell biology. Nat Rev Immunol 12(9):649–661. doi:10.1038/nri3278
Hess Michelini R, Doedens AL, Goldrath AW, Hedrick SM (2013) Differentiation of CD8 memory T cells depends on Foxo1. J Exp Med 210(6):1189–1200. doi:10.1084/jem.20130392
Ho PC, Bihuniak JD, Macintyre AN, Staron M, Liu X, Amezquita R, Tsui YC, Cui G, Micevic G, Perales JC, Kleinstein SH, Abel ED, Insogna KL, Feske S, Locasale JW, Bosenberg MW, Rathmell JC, Kaech SM (2015) Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162(6):1217–1228. doi:10.1016/j.cell.2015.08.012
Hontecillas R, Bassaganya-Riera J (2007) Peroxisome proliferator-activated receptor gamma is required for regulatory CD4+ T cell-mediated protection against colitis. J Immunol 178(5):2940–2949
Hori S, Nomura T, Sakaguchi S (2003) Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609):1057–1061. doi:10.1126/science.1079490
Hosios AM, Hecht VC, Danai LV, Johnson MO, Rathmell JC, Steinhauser ML, Manalis SR, Vander Heiden MG (2016) Amino acids rather than glucose account for the majority of cell mass in proliferating mammalian cells. Dev Cell 36(5):540–549. doi:10.1016/j.devcel.2016.02.012
Housley WJ, Adams CO, Vang AG, Brocke S, Nichols FC, LaCombe M, Rajan TV, Clark RB (2011) Peroxisome proliferator-activated receptor gamma is required for CD4+ T cell-mediated lymphopenia-associated autoimmunity. J Immunol 187(8):4161–4169. doi:10.4049/jimmunol.1101731
Hsieh CS, Lee HM, Lio CW (2012) Selection of regulatory T cells in the thymus. Nat Rev Immunol 12(3):157–167. doi:10.1038/nri3155
Huang D, Li T, Li X, Zhang L, Sun L, He X, Zhong X, Jia D, Song L, Semenza GL, Gao P, Zhang H (2014) HIF-1-mediated suppression of acyl-CoA dehydrogenases and fatty acid oxidation is critical for cancer progression. Cell Rep 8(6):1930–1942. doi:10.1016/j.celrep.2014.08.028
Huh JY, Kim JI, Park YJ, Hwang IJ, Lee YS, Sohn JH, Lee SK, Alfadda AA, Kim SS, Choi SH, Lee DS, Park SH, Seong RH, Choi CS, Kim JB (2013) A novel function of adipocytes in lipid antigen presentation to iNKT cells. Mol Cell Biol 33(2):328–339. doi:10.1128/MCB.00552-12
Hukelmann JL, Anderson KE, Sinclair LV, Grzes KM, Murillo AB, Hawkins PT, Stephens LR, Lamond AI, Cantrell DA (2016) The cytotoxic T cell proteome and its shaping by the kinase mTOR. Nat Immunol 17(1):104–112. doi:10.1038/ni.3314
Hussaarts L, Smits HH, Schramm G, van der Ham AJ, van der Zon GC, Haas H, Guigas B, Yazdanbakhsh M (2013) Rapamycin and omega-1: mTOR-dependent and -independent Th2 skewing by human dendritic cells. Immunol Cell Biol 91(7):486–489. doi:10.1038/icb.2013.31
Huynh A, DuPage M, Priyadharshini B, Sage PT, Quiros J, Borges CM, Townamchai N, Gerriets VA, Rathmell JC, Sharpe AH, Bluestone JA, Turka LA (2015) Control of PI(3) kinase in Treg cells maintains homeostasis and lineage stability. Nat Immunol 16(2):188–196. doi:10.1038/ni.3077
Ikeda S, Saijo S, Murayama MA, Shimizu K, Akitsu A, Iwakura Y (2014) Excess IL-1 signaling enhances the development of Th17 cells by downregulating TGF-beta-induced Foxp3 expression. J Immunol 192(4):1449–1458. doi:10.4049/jimmunol.1300387
Im SS, Yousef L, Blaschitz C, Liu JZ, Edwards RA, Young SG, Raffatellu M, Osborne TF (2011) Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a. Cell Metab 13(5):540–549. doi:10.1016/j.cmet.2011.04.001
Imtiyaz HZ, Williams EP, Hickey MM, Patel SA, Durham AC, Yuan LJ, Hammond R, Gimotty PA, Keith B, Simon MC (2010) Hypoxia-inducible factor 2alpha regulates macrophage function in mouse models of acute and tumor inflammation. J Clin Invest 120(8):2699–2714. doi:10.1172/JCI39506
Infantino V, Convertini P, Cucci L, Panaro MA, Di Noia MA, Calvello R, Palmieri F, Iacobazzi V (2011) The mitochondrial citrate carrier: a new player in inflammation. Biochem J 438(3):433–436. doi:10.1042/BJ20111275
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(7):4476–4486
Janke R, Dodson AE, Rine J (2015) Metabolism and epigenetics. Annu Rev Cell Dev Biol 31:473–496. doi:10.1146/annurev-cellbio-100814-125544
Jantsch J, Chakravortty D, Turza N, Prechtel AT, Buchholz B, Gerlach RG, Volke M, Glasner J, Warnecke C, Wiesener MS, Eckardt KU, Steinkasserer A, Hensel M, Willam C (2008) Hypoxia and hypoxia-inducible factor-1 alpha modulate lipopolysaccharide-induced dendritic cell activation and function. J Immunol 180(7):4697–4705
Jeffery LE, Burke F, Mura M, Zheng Y, Qureshi OS, Hewison M, Walker LS, Lammas DA, Raza K, Sansom DM (2009) 1,25-Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J Immunol 183(9):5458–5467. doi:10.4049/jimmunol.0803217
Jewell JL, Russell RC, Guan KL (2013) Amino acid signalling upstream of mTOR. Nat Rev Mol Cell Biol 14(3):133–139. doi:10.1038/nrm3522
Ji G, Zhang Y, Yang Q, Cheng S, Hao J, Zhao X, Jiang Z (2012) Genistein suppresses LPS-induced inflammatory response through inhibiting NF-kappaB following AMP kinase activation in RAW 264.7 macrophages. PloS One 7(12):e53101. doi:10.1371/journal.pone.0053101
Jiang H, Westerterp M, Wang C, Zhu Y, Ai D (2014) Macrophage mTORC1 disruption reduces inflammation and insulin resistance in obese mice. Diabetologia 57(11):2393–2404. doi:10.1007/s00125-014-3350-5
Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D, Barnett B, Dent AL, Craft J, Crotty S (2009) Bcl6 and blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325(5943):1006–1010. doi:10.1126/science.1175870
Josefowicz SZ, Lu LF, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564. doi:10.1146/annurev.immunol.25.022106.141623
Kabat AM, Harrison OJ, Riffelmacher T, Moghaddam AE, Pearson CF, Laing A, Abeler-Dorner L, Forman SP, Grencis RK, Sattentau Q, Simon AK, Pott J, Maloy KJ (2016) The autophagy gene Atg16l1 differentially regulates Treg and TH2 cells to control intestinal inflammation. eLife 5:e12444. doi:10.7554/eLife.12444
Kaech SM, Cui W (2012) Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol 12(11):749–761. doi:10.1038/nri3307
Kang SG, Lim HW, Andrisani OM, Broxmeyer HE, Kim CH (2007) Vitamin A metabolites induce gut-homing FoxP3+ regulatory T cells. J Immunol 179(6):3724–3733
Kanno Y, Vahedi G, Hirahara K, Singleton K, O’Shea JJ (2012) Transcriptional and epigenetic control of T helper cell specification: molecular mechanisms underlying commitment and plasticity. Annu Rev Immunol 30:707–731. doi:10.1146/annurev-immunol-020711-075058
Kaplan MH, Hufford MM, Olson MR (2015) The development and in vivo function of T helper 9 cells. Nat Rev Immunol 15(5):295–307. doi:10.1038/nri3824
Kawanaka T, Kubo A, Ikushima H, Sano T, Takegawa Y, Nishitani H (2008) Prognostic significance of HIF-2alpha expression on tumor infiltrating macrophages in patients with uterine cervical cancer undergoing radiotherapy. J Med Invest: JMI 55(1–2):78–86
Kc W, Satpathy AT, Rapaport AS, Briseno CG, Wu X, Albring JC, Russler-Germain EV, Kretzer NM, Durai V, Persaud SP, Edelson BT, Loschko J, Cella M, Allen PM, Nussenzweig MC, Colonna M, Sleckman BP, Murphy TL, Murphy KM (2014) L-Myc expression by dendritic cells is required for optimal T-cell priming. Nature 507(7491):243–247. doi:10.1038/nature12967
Keating R, Hertz T, Wehenkel M, Harris TL, Edwards BA, McClaren JL, Brown SA, Surman S, Wilson ZS, Bradley P, Hurwitz J, Chi H, Doherty PC, Thomas PG, McGargill MA (2013) The kinase mTOR modulates the antibody response to provide cross-protective immunity to lethal infection with influenza virus. Nat Immunol 14(12):1266–1276. doi:10.1038/ni.2741
Keppel MP, Saucier N, Mah AY, Vogel TP, Cooper MA (2015) Activation-specific metabolic requirements for NK cell IFN-gamma production. J Immunol 194(4):1954–1962. doi:10.4049/jimmunol.1402099
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(2):176–184. doi:10.1038/ni.1689
Khattri R, Cox T, Yasayko SA, Ramsdell F (2003) An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 4(4):337–342. doi:10.1038/ni909
Kidani Y, Elsaesser H, Hock MB, Vergnes L, Williams KJ, Argus JP, Marbois BN, Komisopoulou E, Wilson EB, Osborne TF, Graeber TG, Reue K, Brooks DG, Bensinger SJ (2013) Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat Immunol 14(5):489–499. doi:10.1038/ni.2570
Kim I, He YY (2013) Targeting the AMP-activated protein kinase for cancer prevention and therapy. Front Oncol 3:175. doi:10.3389/fonc.2013.00175
Kim J, Kundu M, Viollet B, Guan KL (2011) AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 13(2):132–141. doi:10.1038/ncb2152
Kim JK, Klinger M, Benjamin J, Xiao Y, Erle DJ, Littman DR, Killeen N (2009) Impact of the TCR signal on regulatory T cell homeostasis, function, and trafficking. PLoS One 4(8):e6580. doi:10.1371/journal.pone.0006580
Kim JW, Tchernyshyov I, Semenza GL, Dang CV (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 3(3):177–185. doi:10.1016/j.cmet.2006.02.002
Kimura A, Naka T, Nohara K, Fujii-Kuriyama Y, Kishimoto T (2008) Aryl hydrocarbon receptor regulates Stat1 activation and participates in the development of Th17 cells. Proc Natl Acad Sci U.S.A. 105(28):9721–9726. doi:10.1073/pnas.0804231105
Kinoshita M, Kayama H, Kusu T, Yamaguchi T, Kunisawa J, Kiyono H, Sakaguchi S, Takeda K (2012) Dietary folic acid promotes survival of Foxp3+ regulatory T cells in the colon. J Immunol 189(6):2869–2878. doi:10.4049/jimmunol.1200420
Kleinewietfeld M, Manzel A, Titze J, Kvakan H, Yosef N, Linker RA, Muller DN, Hafler DA (2013) Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature 496(7446):518–522. doi:10.1038/nature11868
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 gamma control of dendritic cell function contributes to development of CD4+ T cell anergy. J Immunol 178(4):2122–2131
Kobayashi T, Shimabukuro-Demoto S, Yoshida-Sugitani R, Furuyama-Tanaka K, Karyu H, Sugiura Y, Shimizu Y, Hosaka T, Goto M, Kato N, Okamura T, Suematsu M, Yokoyama S, Toyama-Sorimachi N (2014) The histidine transporter SLC15A4 coordinates mTOR-dependent inflammatory responses and pathogenic antibody production. Immunity 41(3):375–388. doi:10.1016/j.immuni.2014.08.011
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(23):4742–4749. doi:10.1182/blood-2009-10-249540
Kress TR, Sabo A, Amati B (2015) MYC: connecting selective transcriptional control to global RNA production. Nat Rev Cancer 15(10):593–607. doi:10.1038/nrc3984
Kryczek I, Zhao E, Liu Y, Wang Y, Vatan L, Szeliga W, Moyer J, Klimczak A, Lange A, Zou W (2011) Human TH17 cells are long-lived effector memory cells. Sci Transl Med 3(104):104ra100. doi:10.1126/scitranslmed.3002949
Kunisawa J, Hashimoto E, Ishikawa I, Kiyono H (2012) A pivotal role of vitamin B9 in the maintenance of regulatory T cells in vitro and in vivo. PLoS One 7(2):e32094. doi:10.1371/journal.pone.0032094
Kuo CT, Veselits ML, Leiden JM (1997) LKLF: a transcriptional regulator of single-positive T cell quiescence and survival. Science 277(5334):1986–1990
Kurebayashi Y, Nagai S, Ikejiri A, Ohtani M, Ichiyama K, Baba Y, Yamada T, Egami S, Hoshii T, Hirao A, Matsuda S, Koyasu S (2012) PI3K-Akt-mTORC1-S6K1/2 axis controls Th17 differentiation by regulating Gfi1 expression and nuclear translocation of RORgamma. Cell Rep 1(4):360–373. doi:10.1016/j.celrep.2012.02.007
Kurihara T, Arimochi H, Bhuyan ZA, Ishifune C, Tsumura H, Ito M, Ito Y, Kitamura A, Maekawa Y, Yasutomo K (2015) CD98 heavy chain is a potent positive regulator of CD4+ T cell proliferation and interferon-gamma production in vivo. PLoS One 10(10):e0139692. doi:10.1371/journal.pone.0139692
Kurobe H, Urata M, Ueno M, Ueki M, Ono S, Izawa-Ishizawa Y, Fukuhara Y, Lei Y, Ripen AM, Kanbara T, Aihara K, Ishizawa K, Akaike M, Gonzalez FJ, Tamaki T, Takahama Y, Yoshizumi M, Kitagawa T, Tomita S (2010) Role of hypoxia-inducible factor 1alpha in T cells as a negative regulator in development of vascular remodeling. Arterioscler Thromb Vasc Biol 30(2):210–217. doi:10.1161/ATVBAHA.109.192666
La Cava A, Matarese G (2004) The weight of leptin in immunity. Nat Rev Immunol 4(5):371–379. doi:10.1038/nri1350
Laderoute KR, Amin K, Calaoagan JM, Knapp M, Le T, Orduna J, Foretz M, Viollet B (2006) 5′-AMP-activated protein kinase (AMPK) is induced by low-oxygen and glucose deprivation conditions found in solid-tumor microenvironments. Mol Cell Biol 26(14):5336–5347. doi:10.1128/MCB.00166-06
Lal L, Li Y, Smith J, Sassano A, Uddin S, Parmar S, Tallman MS, Minucci S, Hay N, Platanias LC (2005) Activation of the p70 S6 kinase by all-trans-retinoic acid in acute promyelocytic leukemia cells. Blood 105(4):1669–1677. doi:10.1182/blood-2004-06-2078
Laplante M, Sabatini DM (2009) An emerging role of mTOR in lipid biosynthesis. Curr Biol: CB 19(22):R1046–R1052. doi:10.1016/j.cub.2009.09.058
Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149(2):274–293. doi:10.1016/j.cell.2012.03.017
Larbi A, Zelba H, Goldeck D, Pawelec G (2010) Induction of HIF-1alpha and the glycolytic pathway alters apoptotic and differentiation profiles of activated human T cells. J Leukoc Biol 87(2):265–273. doi:10.1189/jlb.0509304
Lee J, Walsh MC, Hoehn KL, James DE, Wherry EJ, Choi Y (2014) Regulator of fatty acid metabolism, acetyl coenzyme a carboxylase 1, controls T cell immunity. J Immunol 192(7):3190–3199. doi:10.4049/jimmunol.1302985
Lee JE, Walsh MC, Hoehn KL, James DE, Wherry EJ, Choi Y (2015a) Acetyl CoA carboxylase 2 is dispensable for CD8+ T cell responses. PLoS One 10(9):e0137776. doi:10.1371/journal.pone.0137776
Lee JY, Skon CN, Lee YJ, Oh S, Taylor JJ, Malhotra D, Jenkins MK, Rosenfeld MG, Hogquist KA, Jameson SC (2015b) The transcription factor KLF2 restrains CD4(+) T follicular helper cell differentiation. Immunity 42(2):252–264. doi:10.1016/j.immuni.2015.01.013
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(6):743–753. doi:10.1016/j.immuni.2010.06.002
Leek RD, Talks KL, Pezzella F, Turley H, Campo L, Brown NS, Bicknell R, Taylor M, Gatter KC, Harris AL (2002) Relation of hypoxia-inducible factor-2 alpha (HIF-2 alpha) expression in tumor-infiltrative macrophages to tumor angiogenesis and the oxidative thymidine phosphorylase pathway in human breast cancer. Cancer Res 62(5):1326–1329
Levine AG, Arvey A, Jin W, Rudensky AY (2014) Continuous requirement for the TCR in regulatory T cell function. Nat Immunol 15(11):1070–1078. doi:10.1038/ni.3004
Li B, Reynolds JM, Stout RD, Bernlohr DA, Suttles J (2009) Regulation of Th17 differentiation by epidermal fatty acid-binding protein. J Immunol 182(12):7625–7633. doi:10.4049/jimmunol.0804192
Li H, Shi B (2015) Tolerogenic dendritic cells and their applications in transplantation. Cell Mol Immunol 12(1):24–30. doi:10.1038/cmi.2014.52
Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY, Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M (2011) AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab 13(4):376–388. doi:10.1016/j.cmet.2011.03.009
Liang SL, Liu H, Zhou A (2006) Lovastatin-induced apoptosis in macrophages through the Rac1/Cdc42/JNK pathway. J Immunol 177(1):651–656
Liang Y, Cucchetti M, Roncagalli R, Yokosuka T, Malzac A, Bertosio E, Imbert J, Nijman IJ, Suchanek M, Saito T, Wulfing C, Malissen B, Malissen M (2013) The lymphoid lineage-specific actin-uncapping protein Rltpr is essential for costimulation via CD28 and the development of regulatory T cells. Nat Immunol 14(8):858–866. doi:10.1038/ni.2634
Limon JJ, So L, Jellbauer S, Chiu H, Corado J, Sykes SM, Raffatellu M, Fruman DA (2014) mTOR kinase inhibitors promote antibody class switching via mTORC2 inhibition. Proc Natl Acad Sci U.S.A. 111(47):E5076–E5085. doi:10.1073/pnas.1407104111
Lisse TS, Hewison M (2011) Vitamin D: a new player in the world of mTOR signaling. Cell Cycle 10(12):1888–1889. doi:10.4161/cc.10.12.15620
Liston A, Gray DH (2014) Homeostatic control of regulatory T cell diversity. Nat Rev Immunol 14(3):154–165. doi:10.1038/nri3605
Liu SY, Aliyari R, Chikere K, Li G, Marsden MD, Smith JK, Pernet O, Guo H, Nusbaum R, Zack JA, Freiberg AN, Su L, Lee B, Cheng G (2013) Interferon-inducible cholesterol-25-hydroxylase broadly inhibits viral entry by production of 25-hydroxycholesterol. Immunity 38(1):92–105. doi:10.1016/j.immuni.2012.11.005
Locasale JW (2013) Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer 13(8):572–583. doi:10.1038/nrc3557
Lu C, Thompson CB (2012) Metabolic regulation of epigenetics. Cell Metab 16(1):9–17. doi:10.1016/j.cmet.2012.06.001
Lu H, Forbes RA, Verma A (2002) Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. J Biol Chem 277(26):23111–23115. doi:10.1074/jbc.M202487200
Lukashev D, Klebanov B, Kojima H, Grinberg A, Ohta A, Berenfeld L, Wenger RH, Ohta A, Sitkovsky M (2006) Cutting edge: hypoxia-inducible factor 1alpha and its activation-inducible short isoform I.1 negatively regulate functions of CD4+ and CD8+ T lymphocytes. J Immunol 177(8):4962–4965
Luo CT, Liao W, Dadi S, Toure A, Li MO (2016) Graded Foxo1 activity in Treg cells differentiates tumour immunity from spontaneous autoimmunity. Nature 529(7587):532–536. doi:10.1038/nature16486
Lynch L, Nowak M, Varghese B, Clark J, Hogan AE, Toxavidis V, Balk SP, O’Shea D, O’Farrelly C, Exley MA (2012) Adipose tissue invariant NKT cells protect against diet-induced obesity and metabolic disorder through regulatory cytokine production. Immunity 37(3):574–587. doi:10.1016/j.immuni.2012.06.016
Ma Y, Xu L, Rodriguez-Agudo D, Li X, Heuman DM, Hylemon PB, Pandak WM, Ren S (2008) 25-hydroxycholesterol-3-sulfate regulates macrophage lipid metabolism via the LXR/SREBP-1 signaling pathway. Am J Phys Endocrinol Metab 295(6):E1369–E1379. doi:10.1152/ajpendo.90555.2008
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(2):224–236. doi:10.1016/j.immuni.2011.01.012
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(1):61–72. doi:10.1016/j.cmet.2014.05.004
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(8):4187–4198. doi:10.4049/jimmunol.1100367
MacIver NJ, Michalek RD, Rathmell JC (2013) Metabolic regulation of T lymphocytes. Annu Rev Immunol 31:259–283. doi:10.1146/annurev-immunol-032712-095956
Malinarich F, Duan K, Hamid RA, Bijin A, Lin WX, Poidinger M, Fairhurst AM, Connolly JE (2015) High mitochondrial respiration and glycolytic capacity represent a metabolic phenotype of human tolerogenic dendritic cells. J Immunol 194(11):5174–5186. doi:10.4049/jimmunol.1303316
Mangus CW, Massey PR, Fowler DH, Amarnath S (2013) Rapamycin resistant murine th9 cells have a stable in vivo phenotype and inhibit graft-versus-host reactivity. PLoS One 8(8):e72305. doi:10.1371/journal.pone.0072305
Marcais A, Cherfils-Vicini J, Viant C, Degouve S, Viel S, Fenis A, Rabilloud J, Mayol K, Tavares A, Bienvenu J, Gangloff YG, Gilson E, Vivier E, Walzer T (2014) The metabolic checkpoint kinase mTOR is essential for IL-15 signaling during the development and activation of NK cells. Nat Immunol 15(8):749–757. doi:10.1038/ni.2936
Marko AJ, Miller RA, Kelman A, Frauwirth KA (2010) Induction of glucose metabolism in stimulated T lymphocytes is regulated by mitogen-activated protein kinase signaling. PLoS One 5(11):e15425. doi:10.1371/journal.pone.0015425
Mascanfroni ID, Takenaka MC, Yeste A, Patel B, Wu Y, Kenison JE, Siddiqui S, Basso AS, Otterbein LE, Pardoll DM, Pan F, Priel A, Clish CB, Robson SC, Quintana FJ (2015) Metabolic control of type 1 regulatory T cell differentiation by AHR and HIF1-alpha. Nat Med 21(6):638–646. doi:10.1038/nm.3868
Masson N, Ratcliffe PJ (2014) Hypoxia signaling pathways in cancer metabolism: the importance of co-selecting interconnected physiological pathways. Cancer Metab 2(1):3. doi:10.1186/2049-3002-2-3
Masui K, Tanaka K, Akhavan D, Babic I, Gini B, Matsutani T, Iwanami A, Liu F, Villa GR, Gu Y, Campos C, Zhu S, Yang H, Yong WH, Cloughesy TF, Mellinghoff IK, Cavenee WK, Shaw RJ, Mischel PS (2013) mTOR complex 2 controls glycolytic metabolism in glioblastoma through FoxO acetylation and upregulation of c-Myc. Cell Metab 18(5):726–739. doi:10.1016/j.cmet.2013.09.013
Mazumdar J, Hickey MM, Pant DK, Durham AC, Sweet-Cordero A, Vachani A, Jacks T, Chodosh LA, Kissil JL, Simon MC, Keith B (2010) HIF-2alpha deletion promotes Kras-driven lung tumor development. Proc Natl Acad Sci U.S.A. 107(32):14182–14187. doi:10.1073/pnas.1001296107
McNamee EN, Korns Johnson D, Homann D, Clambey ET (2013) Hypoxia and hypoxia-inducible factors as regulators of T cell development, differentiation, and function. Immunol Res 55(1–3):58–70. doi:10.1007/s12026-012-8349-8
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(6):3299–3303. doi:10.4049/jimmunol.1003613
Michalek RD, Gerriets VA, Nichols AG, Inoue M, Kazmin D, Chang CY, Dwyer MA, Nelson ER, Pollizzi KN, Ilkayeva O, Giguere V, Zuercher WJ, Powell JD, Shinohara ML, McDonnell DP, Rathmell JC (2011b) Estrogen-related receptor-alpha is a metabolic regulator of effector T-cell activation and differentiation. Proc Natl Acad Sci U.S.A. 108(45):18348–18353. doi:10.1073/pnas.1108856108
Mihaylova MM, Shaw RJ (2011) The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nat Cell Biol 13(9):1016–1023. doi:10.1038/ncb2329
Milasta S, Dillon CP, Sturm OE, Verbist KC, Brewer TL, Quarato G, Brown SA, Frase S, Janke LJ, Perry SS, Thomas PG, Green DR (2016) Apoptosis-inducing-factor-dependent mitochondrial function is required for T cell but not B cell function. Immunity 44(1):88–102. doi:10.1016/j.immuni.2015.12.002
Mirebeau-Prunier D, Le Pennec S, Jacques C, Gueguen N, Poirier J, Malthiery Y, Savagner F (2010) Estrogen-related receptor alpha and PGC-1-related coactivator constitute a novel complex mediating the biogenesis of functional mitochondria. FEBS J 277(3):713–725. doi:10.1111/j.1742-4658.2009.07516.x
Miyao T, Floess S, Setoguchi R, Luche H, Fehling HJ, Waldmann H, Huehn J, Hori S (2012) Plasticity of Foxp3(+) T cells reflects promiscuous Foxp3 expression in conventional T cells but not reprogramming of regulatory T cells. Immunity 36(2):262–275. doi:10.1016/j.immuni.2011.12.012
Monticelli LA, Buck MD, Flamar AL, Saenz SA, Tait Wojno ED, Yudanin NA, Osborne LC, Hepworth MR, Tran SV, Rodewald HR, Shah H, Cross JR, Diamond JM, Cantu E, Christie JD, Pearce EL, Artis D (2016) Arginase 1 is an innate lymphoid-cell-intrinsic metabolic checkpoint controlling type 2 inflammation. Nat Immunol 17(6):656–665. doi:10.1038/ni.3421
Moore KJ, Rosen ED, Fitzgerald ML, Randow F, Andersson LP, Altshuler D, Milstone DS, Mortensen RM, Spiegelman BM, Freeman MW (2001) The role of PPAR-gamma in macrophage differentiation and cholesterol uptake. Nat Med 7(1):41–47. doi:10.1038/83328
Morrison DK (2012) MAP kinase pathways. Cold Spring Harb Perspect Biol 4(11). doi:10.1101/cshperspect.a011254
Mounier R, Theret M, Arnold L, Cuvellier S, Bultot L, Goransson O, Sanz N, Ferry A, Sakamoto K, Foretz M, Viollet B, Chazaud B (2013) AMPKalpha1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration. Cell Metab 18(2):251–264. doi:10.1016/j.cmet.2013.06.017
Mungai PT, Waypa GB, Jairaman A, Prakriya M, Dokic D, Ball MK, Schumacker PT (2011) Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels. Mol Cell Biol 31(17):3531–3545. doi:10.1128/MCB.05124-11
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(5):633–642. doi:10.1016/j.immuni.2005.03.013
Murugaiyan G, Beynon V, Pires Da Cunha A, Joller N, Weiner HL (2012) IFN-gamma limits Th9-mediated autoimmune inflammation through dendritic cell modulation of IL-27. J Immunol 189(11):5277–5283. doi:10.4049/jimmunol.1200808
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(5):692–705. doi:10.1016/j.immuni.2014.04.007
Nath N, Khan M, Paintlia MK, Singh I, Hoda MN, Giri S (2009a) Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. J Immunol 182(12):8005–8014. doi:10.4049/jimmunol.0803563
Nath N, Khan M, Rattan R, Mangalam A, Makkar RS, de Meester C, Bertrand L, Singh I, Chen Y, Viollet B, Giri S (2009b) Loss of AMPK exacerbates experimental autoimmune encephalomyelitis disease severity. Biochem Biophys Res Commun 386(1):16–20. doi:10.1016/j.bbrc.2009.05.106
Nencioni A, Grunebach F, Zobywlaski A, Denzlinger C, Brugger W, Brossart P (2002) Dendritic cell immunogenicity is regulated by peroxisome proliferator-activated receptor gamma. J Immunol 169(3):1228–1235
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(1):121–125
Newsholme P, Gordon S, Newsholme EA (1987) Rates of utilization and fates of glucose, glutamine, pyruvate, fatty acids and ketone bodies by mouse macrophages. Biochem J 242(3):631–636
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(1):211–218
Nishi K, Oda T, Takabuchi S, Oda S, Fukuda K, Adachi T, Semenza GL, Shingu K, Hirota K (2008) LPS induces hypoxia-inducible factor 1 activation in macrophage-differentiated cells in a reactive oxygen species-dependent manner. Antioxid Redox Signal 10(5):983–995. doi:10.1089/ars.2007.1825
Nurieva RI, Chung Y, Martinez GJ, Yang XO, Tanaka S, Matskevitch TD, Wang YH, Dong C (2009) Bcl6 mediates the development of T follicular helper cells. Science 325(5943):1001–1005. doi:10.1126/science.1176676
Nyirenda MH, Sanvito L, Darlington PJ, O’Brien K, Zhang GX, Constantinescu CS, Bar-Or A, Gran B (2011) TLR2 stimulation drives human naive and effector regulatory T cells into a Th17-like phenotype with reduced suppressive function. J Immunol 187(5):2278–2290. doi:10.4049/jimmunol.1003715
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(11):3361–3370. doi:10.1002/eji.201141411
O’Leary JG, Goodarzi M, Drayton DL, von Andrian UH (2006) T cell- and B cell-independent adaptive immunity mediated by natural killer cells. Nat Immunol 7(5):507–516. doi:10.1038/ni1332
O’Neill HM, Maarbjerg SJ, Crane JD, Jeppesen J, Jorgensen SB, Schertzer JD, Shyroka O, Kiens B, van Denderen BJ, Tarnopolsky MA, Kemp BE, Richter EA, Steinberg GR (2011) AMP-activated protein kinase (AMPK) beta1beta2 muscle null mice reveal an essential role for AMPK in maintaining mitochondrial content and glucose uptake during exercise. Proc Natl Acad Sci U.S.A. 108(38):16092–16097. doi:10.1073/pnas.1105062108
O’Neill LA, Golenbock D, Bowie AG (2013) The history of toll-like receptors – redefining innate immunity. Nat Rev Immunol 13(6):453–460. doi:10.1038/nri3446
O’Neill LA, Hardie DG (2013) Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493(7432):346–355. doi:10.1038/nature11862
O’Rourke AM, Rider CC (1989) Glucose, glutamine and ketone body utilisation by resting and concanavalin A activated rat splenic lymphocytes. Biochim Biophys Acta 1010(3):342–345
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, Birnbaum MJ, Pearce EJ, Pearce EL (2014) Memory CD8(+) T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41(1):75–88. doi:10.1016/j.immuni.2014.06.005
O’Sullivan TE, Johnson LR, Kang HH, Sun JC (2015) BNIP3- and BNIP3L-mediated mitophagy promotes the generation of natural killer cell memory. Immunity 43(2):331–342. doi:10.1016/j.immuni.2015.07.012
Odegaard JI, Ricardo-Gonzalez RR, Goforth MH, Morel CR, Subramanian V, Mukundan L, Red Eagle A, Vats D, Brombacher F, Ferrante AW, Chawla A (2007) Macrophage-specific PPARgamma controls alternative activation and improves insulin resistance. Nature 447(7148):1116–1120. doi:10.1038/nature05894
Oestreich KJ, Mohn SE, Weinmann AS (2012) Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile. Nat Immunol 13(4):405–411. doi:10.1038/ni.2242
Oestreich KJ, Read KA, Gilbertson SE, Hough KP, McDonald PW, Krishnamoorthy V, Weinmann AS (2014) Bcl-6 directly represses the gene program of the glycolysis pathway. Nat Immunol 15(10):957–964. doi:10.1038/ni.2985
Ohkura N, Hamaguchi M, Morikawa H, Sugimura K, Tanaka A, Ito Y, Osaki M, Tanaka Y, Yamashita R, Nakano N, Huehn J, Fehling HJ, Sparwasser T, Nakai K, Sakaguchi S (2012) T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37(5):785–799. doi:10.1016/j.immuni.2012.09.010
Ohtani M, Nagai S, Kondo S, Mizuno S, Nakamura K, Tanabe M, Takeuchi T, Matsuda S, Koyasu S (2008) Mammalian target of rapamycin and glycogen synthase kinase 3 differentially regulate lipopolysaccharide-induced interleukin-12 production in dendritic cells. Blood 112(3):635–643. doi:10.1182/blood-2008-02-137430
Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek SE, Salpekar A, Waterfield MD, Smith AJ, Vanhaesebroeck B (2002) Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science 297(5583):1031–1034. doi:10.1126/science.1073560
Okkenhaug K, Patton DT, Bilancio A, Garcon F, Rowan WC, Vanhaesebroeck B (2006) The p110delta isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells. J Immunol 177(8):5122–5128
Orsini H, Araujo LP, Maricato JT, Guereschi MG, Mariano M, Castilho BA, Basso AS (2014) GCN2 kinase plays an important role triggering the remission phase of experimental autoimmune encephalomyelitis (EAE) in mice. Brain Behav Immun 37:177–186. doi:10.1016/j.bbi.2013.12.012
Oshiro N, Rapley J, Avruch J (2014) Amino acids activate mammalian target of rapamycin (mTOR) complex 1 without changing Rag GTPase guanyl nucleotide charging. J Biol Chem 289(5):2658–2674. doi:10.1074/jbc.M113.528505
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(3):358–371. doi:10.1016/j.immuni.2009.02.003
Ouyang W, Liao W, Luo CT, Yin N, Huse M, Kim MV, Peng M, Chan P, Ma Q, Mo Y, Meijer D, Zhao K, Rudensky AY, Atwal G, Zhang MQ, Li MO (2012) Novel Foxo1-dependent transcriptional programs control T(reg) cell function. Nature 491(7425):554–559. doi:10.1038/nature11581
Owen OE, Kalhan SC, Hanson RW (2002) The key role of anaplerosis and cataplerosis for citric acid cycle function. J Biol Chem 277(34):30409–30412. doi:10.1074/jbc.R200006200
Panday A, Sahoo MK, Osorio D, Batra S (2015) NADPH oxidases: an overview from structure to innate immunity-associated pathologies. Cell Mol Immunol 12(1):5–23. doi:10.1038/cmi.2014.89
Pantel A, Teixeira A, Haddad E, Wood EG, Steinman RM, Longhi MP (2014) Direct type I IFN but not MDA5/TLR3 activation of dendritic cells is required for maturation and metabolic shift to glycolysis after poly IC stimulation. PLoS Biol 12(1):e1001759. doi:10.1371/journal.pbio.1001759
Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC (2006) HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab 3(3):187–197. doi:10.1016/j.cmet.2006.01.012
Park H, Tsang M, Iritani BM, Bevan MJ (2014) Metabolic regulator Fnip1 is crucial for iNKT lymphocyte development. Proc Natl Acad Sci U.S.A. 111(19):7066–7071. doi:10.1073/pnas.1406473111
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(1):80–93. doi:10.1038/mi.2014.44
Park Y, Jin HS, Lopez J, Elly C, Kim G, Murai M, Kronenberg M, Liu YC (2013) TSC1 regulates the balance between effector and regulatory T cells. J Clin Invest 123(12):5165–5178. doi:10.1172/JCI69751
Park YH, Wood G, Kastner DL, Chae JJ (2016) Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol 17(8):914–921. doi:10.1038/ni.3457
Parmigiani A, Nourbakhsh A, Ding B, Wang W, Kim YC, Akopiants K, Guan KL, Karin M, Budanov AV (2014) Sestrins inhibit mTORC1 kinase activation through the GATOR complex. Cell Rep 9(4):1281–1291. doi:10.1016/j.celrep.2014.10.019
Parra V, Verdejo HE, Iglewski M, Del Campo A, Troncoso R, Jones D, Zhu Y, Kuzmicic J, Pennanen C, Lopez-Crisosto C, Jana F, Ferreira J, Noguera E, Chiong M, Bernlohr DA, Klip A, Hill JA, Rothermel BA, Abel ED, Zorzano A, Lavandero S (2014) Insulin stimulates mitochondrial fusion and function in cardiomyocytes via the Akt-mTOR-NFkappaB-Opa-1 signaling pathway. Diabetes 63(1):75–88. doi:10.2337/db13-0340
Pearce EJ, Everts B (2015) Dendritic cell metabolism. Nat Rev Immunol 15(1):18–29. doi:10.1038/nri3771
Pearce EL, Pearce EJ (2013) Metabolic pathways in immune cell activation and quiescence. Immunity 38(4):633–643. doi:10.1016/j.immuni.2013.04.005
Pearce EL, Poffenberger MC, Chang CH, Jones RG (2013) Fueling immunity: insights into metabolism and lymphocyte function. Science 342(6155):1242454. doi:10.1126/science.1242454
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(7251):103–107. doi:10.1038/nature08097
Peng M, Yin N, Li MO (2014) Sestrins function as guanine nucleotide dissociation inhibitors for Rag GTPases to control mTORC1 signaling. Cell 159(1):122–133. doi:10.1016/j.cell.2014.08.038
Penna G, Roncari A, Amuchastegui S, Daniel KC, Berti E, Colonna M, Adorini L (2005) Expression of the inhibitory receptor ILT3 on dendritic cells is dispensable for induction of CD4+Foxp3+ regulatory T cells by 1,25-dihydroxyvitamin D3. Blood 106(10):3490–3497. doi:10.1182/blood-2005-05-2044
Peyssonnaux C, Cejudo-Martin P, Doedens A, Zinkernagel AS, Johnson RS, Nizet V (2007a) Cutting edge: essential role of hypoxia inducible factor-1alpha in development of lipopolysaccharide-induced sepsis. J Immunol 178(12):7516–7519
Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, Nizet V, Johnson RS (2007b) Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest 117(7):1926–1932. doi:10.1172/JCI31370
Pochini L, Scalise M, Galluccio M, Indiveri C (2014) Membrane transporters for the special amino acid glutamine: structure/function relationships and relevance to human health. Front Chem 2:61. doi:10.3389/fchem.2014.00061
Pollizzi KN, Patel CH, Sun IH, Oh MH, Waickman AT, Wen J, Delgoffe GM, Powell JD (2015) mTORC1 and mTORC2 selectively regulate CD8(+) T cell differentiation. J Clin Invest 125(5):2090–2108. doi:10.1172/JCI77746
Pollizzi KN, Sun IH, Patel CH, Lo YC, Oh MH, Waickman AT, Tam AJ, Blosser RL, Wen J, Delgoffe GM, Powell JD (2016) Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8(+) T cell differentiation. Nat Immunol 17(6):704–711. doi:10.1038/ni.3438
Procaccini C, Carbone F, Di Silvestre D, Brambilla F, De Rosa V, Galgani M, Faicchia D, Marone G, Tramontano D, Corona M, Alviggi C, Porcellini A, La Cava A, Mauri P, Matarese G (2016) The proteomic landscape of human ex vivo regulatory and conventional T cells reveals specific metabolic requirements. Immunity 44(2):406–421. doi:10.1016/j.immuni.2016.01.028
Procaccini C, De Rosa V, Galgani M, Abanni L, Cali G, Porcellini A, Carbone F, Fontana S, Horvath TL, La Cava A, Matarese G (2010) An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 33(6):929–941. doi:10.1016/j.immuni.2010.11.024
Qu P, Du H, Wilkes DS, Yan C (2009) Critical roles of lysosomal acid lipase in T cell development and function. Am J Pathol 174(3):944–956. doi:10.2353/ajpath.2009.080562
Raikwar HP, Muthian G, Rajasingh J, Johnson C, Bright JJ (2005) PPARgamma antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis. J Neuroimmunol 167(1–2):99–107. doi:10.1016/j.jneuroim.2005.06.026
Rao E, Zhang Y, Zhu G, Hao J, Persson XM, Egilmez NK, Suttles J, Li B (2015) Deficiency of AMPK in CD8+ T cells suppresses their anti-tumor function by inducing protein phosphatase-mediated cell death. Oncotarget 6(10):7944–7958. doi:10.18632/oncotarget.3501
Rao RR, Li Q, Gubbels Bupp MR, Shrikant PA (2012) Transcription factor Foxo1 represses T-bet-mediated effector functions and promotes memory CD8(+) T cell differentiation. Immunity 36(3):374–387. doi:10.1016/j.immuni.2012.01.015
Rao RR, Li Q, Odunsi K, Shrikant PA (2010) The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity 32(1):67–78. doi:10.1016/j.immuni.2009.10.010
Rathmell JC, Vander Heiden MG, Harris MH, Frauwirth KA, Thompson CB (2000) In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability. Mol Cell 6(3):683–692
Ravitz MJ, Chen L, Lynch M, Schmidt EV (2007) C-myc repression of TSC2 contributes to control of translation initiation and Myc-induced transformation. Cancer Res 67(23):11209–11217. doi:10.1158/0008-5472.CAN-06-4351
Ray JP, Staron MM, Shyer JA, Ho PC, Marshall HD, Gray SM, Laidlaw BJ, Araki K, Ahmed R, Kaech SM, Craft J (2015) The interleukin-2-mTORc1 kinase axis defines the signaling, differentiation, and metabolism of T helper 1 and follicular B helper T cells. Immunity 43(4):690–702. doi:10.1016/j.immuni.2015.08.017
Reboldi A, Dang EV, McDonald JG, Liang G, Russell DW, Cyster JG (2014) Inflammation. 25-Hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type I interferon. Science 345(6197):679–684. doi:10.1126/science.1254790
Rocher C, Singla DK (2013) SMAD-PI3K-Akt-mTOR pathway mediates BMP-7 polarization of monocytes into M2 macrophages. PLoS One 8(12):e84009. doi:10.1371/journal.pone.0084009
Rodriguez-Prados JC, Traves PG, Cuenca J, Rico D, Aragones J, Martin-Sanz P, Cascante M, Bosca L (2010) Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J Immunol 185(1):605–614. doi:10.4049/jimmunol.0901698
Rolf J, Zarrouk M, Finlay DK, Foretz M, Viollet B, Cantrell DA (2013) AMPKalpha1: a glucose sensor that controls CD8 T-cell memory. Eur J Immunol 43(4):889–896. doi:10.1002/eji.201243008
Roos D, Loos JA (1973) 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(1):127–135
Rubic T, Lametschwandtner G, Jost S, Hinteregger S, Kund J, Carballido-Perrig N, Schwarzler C, Junt T, Voshol H, Meingassner JG, Mao X, Werner G, Rot A, Carballido JM (2008) Triggering the succinate receptor GPR91 on dendritic cells enhances immunity. Nat Immunol 9(11):1261–1269. doi:10.1038/ni.1657
Rubtsov YP, Niec RE, Josefowicz S, Li L, Darce J, Mathis D, Benoist C, Rudensky AY (2010) Stability of the regulatory T cell lineage in vivo. Science 329(5999):1667–1671. doi:10.1126/science.1191996
Sag D, Carling D, Stout RD, Suttles J (2008) Adenosine 5′-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J Immunol 181(12):8633–8641
Salles J, Chanet A, Giraudet C, Patrac V, Pierre P, Jourdan M, Luiking YC, Verlaan S, Migne C, Boirie Y, Walrand S (2013) 1,25(OH)2-vitamin D3 enhances the stimulating effect of leucine and insulin on protein synthesis rate through Akt/PKB and mTOR mediated pathways in murine C2C12 skeletal myotubes. Mol Nutr Food Res 57(12):2137–2146. doi:10.1002/mnfr.201300074
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(2):290–303. doi:10.1016/j.cell.2010.02.024
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(5882):1496–1501. doi:10.1126/science.1157535
Sang N, Stiehl DP, Bohensky J, Leshchinsky I, Srinivas V, Caro J (2003) MAPK signaling up-regulates the activity of hypoxia-inducible factors by its effects on p300. J Biol Chem 278(16):14013–14019. doi:10.1074/jbc.M209702200
Sarkar S, Germeraad WT, Rouschop KM, Steeghs EM, van Gelder M, Bos GM, Wieten L (2013) Hypoxia induced impairment of NK cell cytotoxicity against multiple myeloma can be overcome by IL-2 activation of the NK cells. PLoS One 8(5):e64835. doi:10.1371/journal.pone.0064835
Sauer K, Cooke MP (2010) Regulation of immune cell development through soluble inositol-1,3,4,5-tetrakisphosphate. Nat Rev Immunol 10(4):257–271. doi:10.1038/nri2745
Sauer S, Bruno L, Hertweck A, Finlay D, Leleu M, Spivakov M, Knight ZA, Cobb BS, Cantrell D, O’Connor E, Shokat KM, Fisher AG, Merkenschlager M (2008) T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci U.S.A 105(22):7797–7802. doi:10.1073/pnas.0800928105
Schmidt AM, Lu W, Sindhava VJ, Huang Y, Burkhardt JK, Yang E, Riese MJ, Maltzman JS, Jordan MS, Kambayashi T (2015) Regulatory T cells require TCR signaling for their suppressive function. J Immunol 194(9):4362–4370. doi:10.4049/jimmunol.1402384
Schmitt E, Germann T, Goedert S, Hoehn P, Huels C, Koelsch S, Kuhn R, Muller W, Palm N, Rude E (1994) IL-9 production of naive CD4+ T cells depends on IL-2, is synergistically enhanced by a combination of TGF-beta and IL-4, and is inhibited by IFN-gamma. J Immunol 153(9):3989–3996
Schmitt E, Klein M, Bopp T (2014) Th9 cells, new players in adaptive immunity. Trends Immunol 35(2):61–68. doi:10.1016/j.it.2013.10.004
Schonle A, Hartl FA, Mentzel J, Noltner T, Rauch KS, Prestipino A, Wohlfeil SA, Apostolova P, Hechinger AK, Melchinger W, Fehrenbach K, Guadamillas MC, Follo M, Prinz G, Ruess AK, Pfeifer D, del Pozo MA, Schmitt-Graeff A, Duyster J, Hippen KI, Blazar BR, Schachtrup K, Minguet S, Zeiser R (2016) Caveolin-1 regulates TCR signal strength and regulatory T-cell differentiation into alloreactive T cells. Blood 127(15):1930–1939. doi:10.1182/blood-2015-09-672428
Semple K, Nguyen A, Yu Y, Wang H, Anasetti C, Yu XZ (2011) Strong CD28 costimulation suppresses induction of regulatory T cells from naive precursors through Lck signaling. Blood 117(11):3096–3103. doi:10.1182/blood-2010-08-301275
Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T, Hildeman DA, Wang CR, Schumacker PT, Licht JD, Perlman H, Bryce PJ, Chandel NS (2013) Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38(2):225–236. doi:10.1016/j.immuni.2012.10.020
Shao W, Espenshade PJ (2012) Expanding roles for SREBP in metabolism. Cell Metab 16(4):414–419. doi:10.1016/j.cmet.2012.09.002
Shen CJ, Yuan ZH, Liu YX, Hu GY (2012) Increased numbers of T helper 17 cells and the correlation with clinicopathological characteristics in multiple myeloma. J Int Med Res 40(2):556–564
Shi LZ, Wang R, Huang G, Vogel P, Neale G, Green DR, Chi H (2011) HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 208(7):1367–1376. doi:10.1084/jem.20110278
Shimobayashi M, Hall MN (2014) Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 15(3):155–162. doi:10.1038/nrm3757
Shimobayashi M, Hall MN (2016) Multiple amino acid sensing inputs to mTORC1. Cell Res 26(1):7–20. doi:10.1038/cr.2015.146
Shin I, Yakes FM, Rojo F, Shin NY, Bakin AV, Baselga J, Arteaga CL (2002) PKB/Akt mediates cell-cycle progression by phosphorylation of p27(Kip1) at threonine 157 and modulation of its cellular localization. Nat Med 8(10):1145–1152. doi:10.1038/nm759
Shrestha S, Yang K, Guy C, Vogel P, Neale G, Chi H (2015) Treg cells require the phosphatase PTEN to restrain TH1 and TFH cell responses. Nat Immunol 16(2):178–187. doi:10.1038/ni.3076
Shrestha S, Yang K, Wei J, Karmaus PWF, Neale G, Chi H (2014) Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs. Proc Natl Acad Sci 111(41):14858–14863. doi:10.1073/pnas.1404264111
Silverstein RL, Febbraio M (2009) CD36, a scavenger receptor involved in immunity, metabolism, angiogenesis, and behavior. Sci Signal 2(72):re3. doi:10.1126/scisignal.272re3
Sim WJ, Ahl PJ, Connolly JE (2016) Metabolism is central to tolerogenic dendritic cell function. Mediat Inflamm 2016:2636701. doi:10.1155/2016/2636701
Sinclair LV, Rolf J, Emslie E, Shi Y-B, 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(5):500–508. doi:10.1038/ni.2556
Singh N, Gurav A, Sivaprakasam S, Brady E, Padia R, Shi H, Thangaraju M, Prasad PD, Manicassamy S, Munn DH, Lee JR, Offermanns S, Ganapathy V (2014) Activation of Gpr109a, receptor for niacin and the commensal metabolite butyrate, suppresses colonic inflammation and carcinogenesis. Immunity 40(1):128–139. doi:10.1016/j.immuni.2013.12.007
Singh R, Xiang Y, Wang Y, Baikati K, Cuervo AM, Luu YK, Tang Y, Pessin JE, Schwartz GJ, Czaja MJ (2009) Autophagy regulates adipose mass and differentiation in mice. J Clin Invest 119(11):3329–3339. doi:10.1172/JCI39228
Skon CN, Lee JY, Anderson KG, Masopust D, Hogquist KA, Jameson SC (2013) Transcriptional downregulation of S1pr1 is required for the establishment of resident memory CD8+ T cells. Nat Immunol 14(12):1285–1293. doi:10.1038/ni.2745
Smith PM, Howitt MR, Panikov N, Michaud M, Gallini CA, Bohlooly YM, Glickman JN, Garrett WS (2013) The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis. Science 341(6145):569–573. doi:10.1126/science.1241165
Sonnenberg GF, Artis D (2015) Innate lymphoid cells in the initiation, regulation and resolution of inflammation. Nat Med 21(7):698–708. doi:10.1038/nm.3892
Sonoda J, Laganiere J, Mehl IR, Barish GD, Chong LW, Li X, Scheffler IE, Mock DC, Bataille AR, Robert F, Lee CH, Giguere V, Evans RM (2007) Nuclear receptor ERR alpha and coactivator PGC-1 beta are effectors of IFN-gamma-induced host defense. Genes Dev 21(15):1909–1920. doi:10.1101/gad.1553007
Sonveaux P, Copetti T, De Saedeleer CJ, Vegran F, Verrax J, Kennedy KM, Moon EJ, Dhup S, Danhier P, Frerart F, Gallez B, Ribeiro A, Michiels C, Dewhirst MW, Feron O (2012) Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis. PLoS One 7(3):e33418. doi:10.1371/journal.pone.0033418
Sowell RT, Rogozinska M, Nelson CE, Vezys V, Marzo AL (2014) Cutting edge: generation of effector cells that localize to mucosal tissues and form resident memory CD8 T cells is controlled by mTOR. J Immunol 193(5):2067–2071. doi:10.4049/jimmunol.1400074
Spirig R, Djafarzadeh S, Regueira T, Shaw SG, von Garnier C, Takala J, Jakob SM, Rieben R, Lepper PM (2010) Effects of TLR agonists on the hypoxia-regulated transcription factor HIF-1alpha and dendritic cell maturation under normoxic conditions. PLoS One 5(6):e0010983. doi:10.1371/journal.pone.0010983
Staron MM, Gray SM, Marshall HD, Parish IA, Chen JH, Perry CJ, Cui G, Li MO, Kaech SM (2014) The transcription factor FoxO1 sustains expression of the inhibitory receptor PD-1 and survival of antiviral CD8(+) T cells during chronic infection. Immunity 41(5):802–814. doi:10.1016/j.immuni.2014.10.013
Staudt V, Bothur E, Klein M, Lingnau K, Reuter S, Grebe N, Gerlitzki B, Hoffmann M, Ulges A, Taube C, Dehzad N, Becker M, Stassen M, Steinborn A, Lohoff M, Schild H, Schmitt E, Bopp T (2010) Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells. Immunity 33(2):192–202. doi:10.1016/j.immuni.2010.07.014
Steinberg GR, Michell BJ, van Denderen BJ, Watt MJ, Carey AL, Fam BC, Andrikopoulos S, Proietto J, Gorgun CZ, Carling D, Hotamisligil GS, Febbraio MA, Kay TW, Kemp BE (2006) Tumor necrosis factor alpha-induced skeletal muscle insulin resistance involves suppression of AMP-kinase signaling. Cell Metab 4(6):465–474. doi:10.1016/j.cmet.2006.11.005
Stone EL, Pepper M, Katayama CD, Kerdiles YM, Lai CY, Emslie E, Lin YC, Yang E, Goldrath AW, Li MO, Cantrell DA, Hedrick SM (2015) ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity 42(2):239–251. doi:10.1016/j.immuni.2015.01.017
Sukumar M, Liu J, Ji Y, Subramanian M, Crompton JG, Yu Z, Roychoudhuri R, Palmer DC, Muranski P, Karoly ED, Mohney RP, Klebanoff CA, Lal A, Finkel T, Restifo NP, Gattinoni L (2013) Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J Clin Invest 123(10):4479–4488. doi:10.1172/JCI69589
Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y (2007) Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 204(8):1775–1785. doi:10.1084/jem.20070602
Sun JC, Beilke JN, Lanier LL (2009) Adaptive immune features of natural killer cells. Nature 457(7229):557–561. doi:10.1038/nature07665
Sun X, Kanwar JR, Leung E, Lehnert K, Wang D, Krissansen GW (2001) Gene transfer of antisense hypoxia inducible factor-1 alpha enhances the therapeutic efficacy of cancer immunotherapy. Gene Ther 8(8):638–645. doi:10.1038/sj.gt.3301388
Swamy M, Beck-Garcia K, Beck-Garcia E, Hartl FA, Morath A, Yousefi OS, Dopfer EP, Molnar E, Schulze AK, Blanco R, Borroto A, Martin-Blanco N, Alarcon B, Hofer T, Minguet S, Schamel WW (2016) A cholesterol-based allostery model of T cell receptor phosphorylation. Immunity 44(5):1091–1101. doi:10.1016/j.immuni.2016.04.011
Szatmari I, Gogolak P, Im JS, Dezso B, Rajnavolgyi E, Nagy L (2004) Activation of PPARgamma specifies a dendritic cell subtype capable of enhanced induction of iNKT cell expansion. Immunity 21(1):95–106. doi:10.1016/j.immuni.2004.06.003
Takamatsu M, Hirata A, Ohtaki H, Hoshi M, Ando T, Ito H, Hatano Y, Tomita H, Kuno T, Saito K, Seishima M, Hara A (2015) Inhibition of indoleamine 2,3-dioxygenase 1 expression alters immune response in colon tumor microenvironment in mice. Cancer Sci 106(8):1008–1015. doi:10.1111/cas.12705
Takeda N, O’Dea EL, Doedens A, Kim JW, Weidemann A, Stockmann C, Asagiri M, Simon MC, Hoffmann A, Johnson RS (2010) Differential activation and antagonistic function of HIF-{alpha} isoforms in macrophages are essential for NO homeostasis. Genes Dev 24(5):491–501. doi:10.1101/gad.1881410
Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL (2000) The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 157(2):411–421
Tamas 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(7):1665–1670. doi:10.1084/jem.20052469
Tamas 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(1):242–253. doi:10.1002/eji.200939677
Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G, Frezza C, Bernard NJ, Kelly B, Foley NH, Zheng L, Gardet A, Tong Z, Jany SS, Corr SC, Haneklaus M, Caffrey BE, Pierce K, Walmsley S, Beasley FC, Cummins E, Nizet V, Whyte M, Taylor CT, Lin H, Masters SL, Gottlieb E, Kelly VP, Clish C, Auron PE, Xavier RJ, O’Neill LA (2013) Succinate is an inflammatory signal that induces IL-1beta through HIF-1alpha. Nature 496(7444):238–242. doi:10.1038/nature11986
Tato I, Bartrons R, Ventura F, Rosa JL (2011) Amino acids activate mammalian target of rapamycin complex 2 (mTORC2) via PI3K/Akt signaling. J Biol Chem 286(8):6128–6142. doi:10.1074/jbc.M110.166991
Tejera MM, Kim EH, Sullivan JA, Plisch EH, Suresh M (2013) FoxO1 controls effector-to-memory transition and maintenance of functional CD8 T cell memory. J Immunol 191(1):187–199. doi:10.4049/jimmunol.1300331
Thiel M, Caldwell CC, Kreth S, Kuboki S, Chen P, Smith P, Ohta A, Lentsch AB, Lukashev D, Sitkovsky MV (2007) Targeted deletion of HIF-1alpha gene in T cells prevents their inhibition in hypoxic inflamed tissues and improves septic mice survival. PLoS One 2(9):e853. doi:10.1371/journal.pone.0000853
Thurnher M, Gruenbacher G (2015) T lymphocyte regulation by mevalonate metabolism. Sci Signal 8(370):re4. doi:10.1126/scisignal.2005970
Toschi A, Lee E, Gadir N, Ohh M, Foster DA (2008) Differential dependence of hypoxia-inducible factors 1 alpha and 2 alpha on mTORC1 and mTORC2. J Biol Chem 283(50):34495–34499. doi:10.1074/jbc.C800170200
Tripmacher R, Gaber T, Dziurla R, Haupl T, Erekul K, Grutzkau A, Tschirschmann M, Scheffold A, Radbruch A, Burmester GR, Buttgereit F (2008) Human CD4(+) T cells maintain specific functions even under conditions of extremely restricted ATP production. Eur J Immunol 38(6):1631–1642. doi:10.1002/eji.200738047
Troutman TD, Hu W, Fulenchek S, Yamazaki T, Kurosaki T, Bazan JF, Pasare C (2012) Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt. Proc Natl Acad Sci U.S.A. 109(1):273–278. doi:10.1073/pnas.1118579109
Tsun ZY, Bar-Peled L, Chantranupong L, Zoncu R, Wang T, Kim C, Spooner E, Sabatini DM (2013) The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol Cell 52(4):495–505. doi:10.1016/j.molcel.2013.09.016
Turcotte LP, Raney MA, Todd MK (2005) ERK1/2 inhibition prevents contraction-induced increase in plasma membrane FAT/CD36 content and FA uptake in rodent muscle. Acta Physiol Scand 184(2):131–139. doi:10.1111/j.1365-201X.2005.01445.x
Vahl JC, Drees C, Heger K, Heink S, Fischer JC, Nedjic J, Ohkura N, Morikawa H, Poeck H, Schallenberg S, Riess D, Hein MY, Buch T, Polic B, Schonle A, Zeiser R, Schmitt-Graff A, Kretschmer K, Klein L, Korn T, Sakaguchi S, Schmidt-Supprian M (2014) Continuous T cell receptor signals maintain a functional regulatory T cell pool. Immunity 41(5):722–736. doi:10.1016/j.immuni.2014.10.012
van der Bliek AM, Shen Q, Kawajiri S (2013) Mechanisms of mitochondrial fission and fusion. Cold Spring Harb Perspect Biol 5(6). doi:10.1101/cshperspect.a011072
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(1):68–78. doi:10.1016/j.immuni.2011.12.007
Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, Christofk HR, Wagner G, Rabinowitz JD, Asara JM, Cantley LC (2010) Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science 329(5998):1492–1499. doi:10.1126/science.1188015
Vasanthakumar A, Moro K, Xin A, Liao Y, Gloury R, Kawamoto S, Fagarasan S, Mielke LA, Afshar-Sterle S, Masters SL, Nakae S, Saito H, Wentworth JM, Li P, Liao W, Leonard WJ, Smyth GK, Shi W, Nutt SL, Koyasu S, Kallies A (2015) The transcriptional regulators IRF4, BATF and IL-33 orchestrate development and maintenance of adipose tissue-resident regulatory T cells. Nat Immunol 16(3):276–285. doi:10.1038/ni.3085
Vats D, Mukundan L, Odegaard JI, Zhang L, Smith KL, Morel CR, Wagner RA, Greaves DR, Murray PJ, Chawla A (2006) Oxidative metabolism and PGC-1beta attenuate macrophage-mediated inflammation. Cell Metab 4(1):13–24. doi:10.1016/j.cmet.2006.05.011
Veldhoen M, Hirota K, Westendorf AM, Buer J, Dumoutier L, Renauld JC, Stockinger B (2008a) The aryl hydrocarbon receptor links TH17-cell-mediated autoimmunity to environmental toxins. Nature 453(7191):106–109. doi:10.1038/nature06881
Veldhoen M, Uyttenhove C, van Snick J, Helmby H, Westendorf A, Buer J, Martin B, Wilhelm C, Stockinger B (2008b) Transforming growth factor-beta ‘reprograms’ the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol 9(12):1341–1346. doi:10.1038/ni.1659
Verbist KC, Guy CS, Milasta S, Liedmann S, Kaminski MM, Wang R, Green DR (2016) Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature 532(7599):389–393. doi:10.1038/nature17442
Vousden KH, Lane DP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8(4):275–283. doi:10.1038/nrm2147
Wahli W, Michalik L (2012) PPARs at the crossroads of lipid signaling and inflammation. Trends Endocrinol Metab 23(7):351–363. doi:10.1016/j.tem.2012.05.001
Wang F, Alain T, Szretter KJ, Stephenson K, Pol JG, Atherton MJ, Hoang HD, Fonseca BD, Zakaria C, Chen L, Rangwala Z, Hesch A, Chan ES, Tuinman C, Suthar MS, Jiang Z, Ashkar AA, Thomas G, Kozma SC, Gale M Jr, Fitzgerald KA, Diamond MS, Mossman K, Sonenberg N, Wan Y, Lichty BD (2016a) S6K-STING interaction regulates cytosolic DNA-mediated activation of the transcription factor IRF3. Nat Immunol 17(5):514–522. doi:10.1038/ni.3433
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(6):871–882. doi:10.1016/j.immuni.2011.09.021
Wang R, Green DR (2012) Metabolic checkpoints in activated T cells. Nat Immunol 13(10):907–915. doi:10.1038/ni.2386
Wang S, Charbonnier LM, Noval Rivas M, Georgiev P, Li N, Gerber G, Bry L, Chatila TA (2015a) MyD88 adaptor-dependent microbial sensing by regulatory T cells promotes mucosal tolerance and enforces commensalism. Immunity 43(2):289–303. doi:10.1016/j.immuni.2015.06.014
Wang S, Tsun ZY, Wolfson RL, Shen K, Wyant GA, Plovanich ME, Yuan ED, Jones TD, Chantranupong L, Comb W, Wang T, Bar-Peled L, Zoncu R, Straub C, Kim C, Park J, Sabatini BL, Sabatini DM (2015b) Metabolism. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1. Science 347(6218):188–194. doi:10.1126/science.1257132
Wang S, Xia P, Huang G, Zhu P, Liu J, Ye B, Du Y, Fan Z (2016b) FoxO1-mediated autophagy is required for NK cell development and innate immunity. Nat Commun 7:11023. doi:10.1038/ncomms11023
Wang X, Wang W, Xu J, Wu S, Le Q (2015c) All-trans retinoid acid promotes allogeneic corneal graft survival in mice by regulating Treg-Th17 balance in the presence of TGF-beta. BMC Immunol 16:17. doi:10.1186/s12865-015-0082-3
Wang Y, Bi Y, Chen X, Li C, Li Y, Zhang Z, Wang J, Lu Y, Yu Q, Su H, Yang H, Liu G (2016c) Histone deacetylase SIRT1 negatively regulates the differentiation of interleukin-9-producing CD4(+) T cells. Immunity 44(6):1337–1349. doi:10.1016/j.immuni.2016.05.009
Wang Y, Huang G, Zeng H, Yang K, Lamb RF, Chi H (2013) Tuberous sclerosis 1 (Tsc1)-dependent metabolic checkpoint controls development of dendritic cells. Proc Natl Acad Sci USA 110(50):E4894–E4903. doi:10.1073/pnas.1308905110
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(21):5952–5962. doi:10.1128/MCB.00585-09
Weber JP, Fuhrmann F, Feist RK, Lahmann A, Al Baz MS, Gentz LJ, Vu Van D, Mages HW, Haftmann C, Riedel R, Grun JR, Schuh W, Kroczek RA, Radbruch A, Mashreghi MF, Hutloff A (2015) ICOS maintains the T follicular helper cell phenotype by down-regulating Kruppel-like factor 2. J Exp Med 212(2):217–233. doi:10.1084/jem.20141432
Wei H, Geng J, Shi B, Liu Z, Wang YH, Stevens AC, Sprout SL, Yao M, Wang H, Hu H (2016a) Cutting edge: Foxp1 controls naive CD8+ T cell quiescence by simultaneously repressing key pathways in cellular metabolism and cell cycle progression. J Immunol 196(9):3537–3541. doi:10.4049/jimmunol.1501896
Wei J, Long L, Yang K, Guy C, Shrestha S, Chen Z, Wu C, Vogel P, Neale G, Green DR, Chi H (2016b) Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat Immunol 17(3):277–285. doi:10.1038/ni.3365
Wei J, Yang K, Chi H (2014) Cutting edge: discrete functions of mTOR signaling in invariant NKT cell development and NKT17 fate decision. J Immunol 193(9):4297–4301. doi:10.4049/jimmunol.1402042
Wellen KE, Hatzivassiliou G, Sachdeva UM, Bui TV, Cross JR, Thompson CB (2009) ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324(5930):1076–1080. doi:10.1126/science.1164097
West AP, Shadel GS, Ghosh S (2011) Mitochondria in innate immune responses. Nat Rev Immunol 11(6):389–402. doi:10.1038/nri2975
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(4):1437–1446. doi:10.1091/mbc.E06-07-0593
Wildin RS, Ramsdell F, Peake J, Faravelli F, Casanova JL, Buist N, Levy-Lahad E, Mazzella M, Goulet O, Perroni L, Bricarelli FD, Byrne G, McEuen M, Proll S, Appleby M, Brunkow ME (2001) X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 27(1):18–20. doi:10.1038/83707
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(4):2101–2111. doi:10.1182/blood-2007-06-096297
Woodland RT, Fox CJ, Schmidt MR, Hammerman PS, Opferman JT, Korsmeyer SJ, Hilbert DM, Thompson CB (2008) Multiple signaling pathways promote B lymphocyte stimulator dependent B-cell growth and survival. Blood 111(2):750–760. doi:10.1182/blood-2007-03-077222
Wu C, Yosef N, Thalhamer T, Zhu C, Xiao S, Kishi Y, Regev A, Kuchroo VK (2013a) Induction of pathogenic TH17 cells by inducible salt-sensing kinase SGK1. Nature 496(7446):513–517. doi:10.1038/nature11984
Wu D, Sanin DE, Everts B, Chen Q, Qiu J, Buck MD, Patterson A, Smith AM, Chang CH, Liu Z, Artyomov MN, Pearce EL, Cella M, Pearce EJ (2016) Type 1 interferons induce changes in core metabolism that are critical for immune function. Immunity 44(6):1325–1336. doi:10.1016/j.immuni.2016.06.006
Wu J, Yang J, Yang K, Wang H, Gorentla B, Shin J, Qiu Y, Que LG, Foster WM, Xia Z, Chi H, Zhong XP (2014) iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions. J Clin Invest 124(4):1685–1698. doi:10.1172/JCI69780
Wu N, Zheng B, Shaywitz A, Dagon Y, Tower C, Bellinger G, Shen CH, Wen J, Asara J, McGraw TE, Kahn BB, Cantley LC (2013b) AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1. Mol Cell 49(6):1167–1175. doi:10.1016/j.molcel.2013.01.035
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(3):1106–1112. doi:10.4049/jimmunol.1003968
Wu T, Shin HM, Moseman EA, Ji Y, Huang B, Harly C, Sen JM, Berg LJ, Gattinoni L, McGavern DB, Schwartzberg PL (2015) TCF1 is required for the T follicular helper cell response to viral infection. Cell Rep 12(12):2099–2110. doi:10.1016/j.celrep.2015.08.049
Xiao N, Eto D, Elly C, Peng G, Crotty S, Liu YC (2014) The E3 ubiquitin ligase Itch is required for the differentiation of follicular helper T cells. Nat Immunol 15(7):657–666. doi:10.1038/ni.2912
Xu L, Cao Y, Xie Z, Huang Q, Bai Q, Yang X, He R, Hao Y, Wang H, Zhao T, Fan Z, Qin A, Ye J, Zhou X, Ye L, Wu Y (2015) The transcription factor TCF-1 initiates the differentiation of T(FH) cells during acute viral infection. Nat Immunol 16(9):991–999. doi:10.1038/ni.3229
Yamagata K, Daitoku H, Takahashi Y, Namiki K, Hisatake K, Kako K, Mukai H, Kasuya Y, Fukamizu A (2008) Arginine methylation of FOXO transcription factors inhibits their phosphorylation by Akt. Mol Cell 32(2):221–231. doi:10.1016/j.molcel.2008.09.013
Yan D, Farache J, Mingueneau M, Mathis D, Benoist C (2015) Imbalanced signal transduction in regulatory T cells expressing the transcription factor FoxP3. Proc Natl Acad Sci U.S.A. 112(48):14942–14947. doi:10.1073/pnas.1520393112
Yan Y, Zhang GX, Gran B, Fallarino F, Yu S, Li H, Cullimore ML, Rostami A, Xu H (2010) IDO upregulates regulatory T cells via tryptophan catabolite and suppresses encephalitogenic T cell responses in experimental autoimmune encephalomyelitis. J Immunol 185(10):5953–5961. doi:10.4049/jimmunol.1001628
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(9):888–897. doi:10.1038/ni.2068
Yang K, Shrestha S, Zeng H, Karmaus PW, Neale G, Vogel P, Guertin DA, Lamb RF, Chi H (2013a) T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. Immunity 39(6):1043–1056. doi:10.1016/j.immuni.2013.09.015
Yang W, Bai Y, Xiong Y, Zhang J, Chen S, Zheng X, Meng X, Li L, Wang J, Xu C, Yan C, Wang L, Chang CC, Chang TY, Zhang T, Zhou P, Song BL, Liu W, Sun SC, Liu X, Li BL, Xu C (2016) Potentiating the antitumour response of CD8(+) T cells by modulating cholesterol metabolism. Nature 531(7596):651–655. doi:10.1038/nature17412
Yang XO, Zhang H, Kim BS, Niu X, Peng J, Chen Y, Kerketta R, Lee YH, Chang SH, Corry DB, Wang D, Watowich SS, Dong C (2013b) The signaling suppressor CIS controls proallergic T cell development and allergic airway inflammation. Nat Immunol 14(7):732–740. doi:10.1038/ni.2633
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 gamma (PPARgamma) agonists. PPARgamma co-association with transcription factor NFAT. J Biol Chem 275(7):4541–4544
Yang Y, Lovett-Racke AE, Racke MK (2010a) Regulation of immune responses and autoimmune encephalomyelitis by PPARs. PPAR Res 2010:104705. doi:10.1155/2010/104705
Yang Z, Kahn BB, Shi H, Xue BZ (2010b) Macrophage alpha1 AMP-activated protein kinase (alpha1AMPK) antagonizes fatty acid-induced inflammation through SIRT1. J Biol Chem 285(25):19051–19059. doi:10.1074/jbc.M110.123620
Ye J, DeBose-Boyd RA (2011) Regulation of cholesterol and fatty acid synthesis. Cold Spring Harb Perspect Biol 3(7). doi:10.1101/cshperspect.a004754
Yin Y, Choi SC, Xu Z, Perry DJ, Seay H, Croker BP, Sobel ES, Brusko TM, Morel L (2015) Normalization of CD4+ T cell metabolism reverses lupus. Sci Transl Med 7(274):274ra218. doi:10.1126/scitranslmed.aaa0835
York AG, Williams KJ, Argus JP, Zhou QD, Brar G, Vergnes L, Gray EE, Zhen A, Wu NC, Yamada DH, Cunningham CR, Tarling EJ, Wilks MQ, Casero D, Gray DH, Yu AK, Wang ES, Brooks DG, Sun R, Kitchen SG, Wu TT, Reue K, Stetson DB, Bensinger SJ (2015) Limiting cholesterol biosynthetic flux spontaneously engages type I IFN signaling. Cell 163(7):1716–1729. doi:10.1016/j.cell.2015.11.045
Zeng H, Cohen S, Guy C, Shrestha S, Neale G, Brown SA, Cloer C, Kishton RJ, Youngblood B, Do M, Li MO, Locasale JW, Rathmell JC, Chi H (2016) mTORC1 and mTORC2 kinase signaling and glucose metabolism drive follicular helper T cell differentitiation. Immunity 45:540
Zeng H, Yang K, Cloer C, Neale G, Vogel P, Chi H (2013) mTORC1 couples immune signals and metabolic programming to establish T(reg)-cell function. Nature 499(7459):485–490. doi:10.1038/nature12297
Zhang L, Tschumi BO, Corgnac S, Ruegg MA, Hall MN, Mach JP, Romero P, Donda A (2014) Mammalian target of rapamycin complex 1 orchestrates invariant NKT cell differentiation and effector function. J Immunol 193(4):1759–1765. doi:10.4049/jimmunol.1400769
Zhang L, Zhang H, Li L, Xiao Y, Rao E, Miao Z, Chen H, Sun L, Li H, Liu G, Zhao Y (2012) TSC1/2 signaling complex is essential for peripheral naive CD8+ T cell survival and homeostasis in mice. PLoS One 7(2):e30592. doi:10.1371/journal.pone.0030592
Zhang R, Huynh A, Whitcher G, Chang J, Maltzman JS, Turka LA (2013) An obligate cell-intrinsic function for CD28 in Tregs. J Clin Invest 123(2):580–593. doi:10.1172/JCI65013
Zheng Y, Delgoffe GM, Meyer CF, Chan W, Powell JD (2009) Anergic T cells are metabolically anergic. J Immunol 183(10):6095–6101. doi:10.4049/jimmunol.0803510
Zheng Y, Josefowicz S, Chaudhry A, Peng XP, Forbush K, Rudensky AY (2010) Role of conserved non-coding DNA elements in the Foxp3 gene in regulatory T-cell fate. Nature 463(7282):808–812. doi:10.1038/nature08750
Zhou X, Bailey-Bucktrout SL, Jeker LT, Penaranda C, Martinez-Llordella M, Ashby M, Nakayama M, Rosenthal W, Bluestone JA (2009) Instability of the transcription factor Foxp3 leads to the generation of pathogenic memory T cells in vivo. Nat Immunol 10(9):1000–1007. doi:10.1038/ni.1774
Zhu L, Yang T, Li L, Sun L, Hou Y, Hu X, Zhang L, Tian H, Zhao Q, Peng J, Zhang H, Wang R, Yang Z, Zhao Y (2014) TSC1 controls macrophage polarization to prevent inflammatory disease. Nat Commun 5:4696. doi:10.1038/ncomms5696
Zinzalla V, Stracka D, Oppliger W, Hall MN (2011) Activation of mTORC2 by association with the ribosome. Cell 144(5):757–768. doi:10.1016/j.cell.2011.02.014
Zizzo G, Cohen PL (2015) The PPAR-gamma antagonist GW9662 elicits differentiation of M2c-like cells and upregulation of the MerTK/Gas6 axis: a key role for PPAR-gamma in human macrophage polarization. J Inflamm 12:36. doi:10.1186/s12950-015-0081-4
Zoncu R, Bar-Peled L, Efeyan A, Wang S, Sancak Y, Sabatini DM (2011) mTORC1 senses lysosomal amino acids through an inside-out mechanism that requires the vacuolar H(+)-ATPase. Science 334(6056):678–683. doi:10.1126/science.1207056
Zong Y, Sun L, Liu B, Deng YS, Zhan D, Chen YL, He Y, Liu J, Zhang ZJ, Sun J, Lu D (2012) Resveratrol inhibits LPS-induced MAPKs activation via activation of the phosphatidylinositol 3-kinase pathway in murine RAW 264.7 macrophage cells. PloS One 7(8):e44107. doi:10.1371/journal.pone.0044107
Acknowledgments
This work was supported by the Hartwell Foundation Biomedical Research Fellowship (N.M.C.) and NIH AI105887, AI101407, CA176624, and NS064599, America Asthma Foundation, and Crohn’s & Colitis Foundation of America (to H.C.).
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer Science+Business Media B.V.
About this chapter
Cite this chapter
Chapman, N.M., Shrestha, S., Chi, H. (2017). Metabolism in Immune Cell Differentiation and Function. In: Li, B., Pan, F. (eds) Immune Metabolism in Health and Tumor. Advances in Experimental Medicine and Biology, vol 1011. Springer, Dordrecht. https://doi.org/10.1007/978-94-024-1170-6_1
Download citation
DOI: https://doi.org/10.1007/978-94-024-1170-6_1
Published:
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-024-1168-3
Online ISBN: 978-94-024-1170-6
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)