Metabolism along the life journey of T cells

Abstract

T cells are one of few cell types in adult mammals that can proliferate extensively and differentiate diversely upon stimulation, which serves as an excellent example to dissect the metabolic basis of cell fate decisions. During the last decade, there has been an explosion of research into the metabolic control of T-cell responses. The roles of common metabolic pathways, including glycolysis, lipid metabolism, and mitochondrial oxidative phosphorylation, in T-cell responses have been well characterized, and their mechanisms of action are starting to emerge. In this review, we present several considerations for T-cell metabolism-focused research, while providing an overview of the metabolic control of T-cell fate decisions during their life journey. We try to synthesize principles that explain the causal relationship between cellular metabolism and T-cell fate decision. We also discuss key unresolved questions and challenges in targeting T-cell metabolism to treat disease.

Keywords

T cells / immunometabolism / glycolysis / OXPHOS / FAO / acetyl-CoA

References

[1] Hotamisligil GS . Foundations of immunometabolism and implications for metabolic health and disease. Immunity 2017; 47: 406- 20.

[2] Lee YS , Wollam J , Olefsky JM . An integrated view of immunometabolism. Cell 2018; 172: 22- 40.

[3] Warburg O , Gawehn K , Geissler AW . Stoffwechsel der weiβen Blutzellen. Z Naturforsch B 1958; 13: 515- 6.

[4] Warburg O , Posener K , Negelein E . On the metabolism of carcinoma cells. Biochem Z 1924; 152: 309- 44.

[5] Yoon H , Kim TS , Braciale TJ . The cell cycle time of CD8+ T cells responding in vivo is controlled by the type of antigenic stimulus. PLoS One 2010; 5: e15423.

[6] Zhang N , Bevan MJ . CD8+ T cells:foot soldiers of the immune system. Immunity 2011; 35: 161- 8.

[7] Fox CJ , Hammerman PS , Thompson CB . Fuel feeds function:energy metabolism and the T-cell response. Nat Rev Immunol 2005; 5: 844- 52.

[8] Buck MD , Sowell RT , Kaech SMet al. Metabolic instruction of immunity. Cell 2017; 169: 570- 86.

[9] O'Neill LAJ , Pearce EJ . Immunometabolism governs dendritic cell and macrophage function. J Exp Med 2016; 213: 15- 23.

[10] Nish SA , Lin WHW , Reiner SL . Lymphocyte fate and metabolism:a clonal balancing act. Trends Cell Biol 2017; 27: 946- 54.

[11] Pearce EL , Poffenberger MC , Chang CHet al. Fueling immunity:insights into metabolism and lymphocyte function. Science 2013; 342: 1242454.

[12] Efeyan A , Comb WC , Sabatini DM . Nutrient-sensing mechanisms and pathways. Nature 2015; 517: 302- 10.

[13] Chi H . Regulation and function of mTOR signalling in T cell fate decisions. Nat Rev Immunol 2012; 12: 325- 38.

[14] Ma EH , Poffenberger MC , Wong AHet al. The role of AMPK in T cell metabolism and function. Curr Opin Immunol 2017; 46: 45- 52.

[15] Pan C , Li B , Simon MC . Moonlighting functions of metabolic enzymes and metabolites in cancer. Mol Cell 2021; 81: 3760- 74.

[16] Chang CH , Curtis JD , Maggi LBet al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 2013; 153: 1239- 51.

[17] Hu Z , Qu G , Yu Xet al. Acylglycerol kinase maintains metabolic state and immune responses of CD8+ T cells. Cell Metab 2019; 30: 290- 302.e5.

[18] Guppy M , Greiner E , Brand K . The role of the Crabtree effect and an endogenous fuel in the energy metabolism of resting and proliferating thymocytes. Eur J Biochem 1993; 212: 95- 9.

[19] Yang K , Neale G , Green DRet al. The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat Immunol 2011; 12: 888- 97.

[20] Jacobs SR , Herman CE , MacIver NJet al. Glucose uptake is limiting in T cell activation and requires CD28-mediated akt-dependent and independent pathways. J Immunol 2008; 180: 4476- 86.

[21] Lu C , Thompson CB . Metabolic regulation of epigenetics. Cell Metab 2012; 16: 9- 17.

[22] O'Shea JJ , Paul WE . Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 2010; 327: 1098- 102.

[23] Michalek RD , Gerriets VA , Jacobs SRet al. Cutting edge:distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 2011; 186: 3299- 303.

[24] Bailis W , Shyer JA , Zhao Jet al. Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function. Nature 2019; 571: 403- 7.

[25] De RosaV , Galgani M , Porcellini Aet al. Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants. Nat Immunol 2015; 16: 1174- 84.

[26] Hochrein SM , Wu H , Eckstein Met al. The glucose transporter GLUT3 controls T helper 17 cell responses through glycolytic-epigenetic reprogramming. Cell Metab 2022; 34: 516- 32.e11.

[27] Peng M , Yin N , Chhangawala Set al. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 2016; 354: 481- 4.

[28] Xu K , Yin N , Peng Met al. Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses. Immunity 2021; 54: 976- 87.e7.

[29] Raud B , Roy DG , Divakaruni ASet al. Etomoxir actions on regulatory and memory T cells are independent of cpt1a-mediated fatty acid oxidation. Cell Metab 2018; 28: 504- 15.e7.

[30] Divakaruni AS , Hsieh WY , Minarrieta Let al. Etomoxir inhibits macrophage polarization by disrupting CoA homeostasis. Cell Metab 2018; 28: 490- 503.e7.

[31] Germain RN . T-cell development and the CD4-CD8 lineage decision. Nat Rev Immunol 2002; 2: 309- 22.

[32] Shortman K , Egerton M , Spangrude GJet al. The generation and fate of thymocytes. Semin Immunol 1990; 2: 3- 12.

[33] Macintyre AN , Gerriets VA , Nichols AGet al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab 2014; 20: 61- 72.

[34] Takada K , Jameson SC . Naive T cell homeostasis:from awareness of space to a sense of place. Nat Rev Immunol 2009; 9: 823- 32.

[35] Wang YH , Israelsen WJ , Lee Det al. Cell-state-specific metabolic dependency in hematopoiesis and leukemogenesis. Cell 2014; 158: 1309- 23.

[36] Smith-Garvin JE , Koretzky GA , Jordan MS . T cell activation. Annu Rev Immunol 2009; 27: 591- 619.

[37] Sena LA , Li S , Jairaman Aet al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 2013; 38: 225- 36.

[38] Ron-Harel N , Santos D , Ghergurovich JMet al. Mitochondrial biogenesis and proteome remodeling promote one-carbon metabolism for T cell activation. Cell Metab 2016; 24: 104- 17.

[39] Xu K , Yin N , Peng Met al. Glycolysis fuels phosphoinositide 3-kinase signaling to bolster T cell immunity. Science 2021; 371: 405- 410.

[40] Ouyang W , Beckett O , Flavell RAet al. An essential role of the Forkhead-box transcription factor Foxo1 in control of T cell homeostasis and tolerance. Immunity 2009; 30: 358- 71.

[41] Ouyang W , Li MO . Foxo:in command of T lymphocyte homeostasis and tolerance. Trends Immunol 2011; 32: 26- 33.

[42] Kerdiles YM , Beisner DR , Tinoco Ret al. Foxo1 links homing and survival of naive T cells by regulating L-selectin, CCR7 and interleukin 7 receptor. Nat Immunol 2009; 10: 176- 84.

[43] Blattman JN , Antia R , Sourdive DJet al. Estimating the precursor frequency of naive antigen-specific CD8 T cells. J Exp Med 2002; 195: 657- 64.

[44] Sprent J , Surh CD . Normal T cell homeostasis:the conversion of naive cells into memory-phenotype cells. Nat Immunol 2011; 12: 478- 84.

[45] Surh CD , Sprent J . Homeostasis of naive and memory T cells. Immunity 2008; 29: 848- 62.

[46] Zhao HF , Liu Y , Wang Let al. Genome-wide fitness gene identification reveals Roquin as a potent suppressor of CD8 T cell expansion and anti-tumor immunity. Cell Rep 2021; 37: 110083.

[47] Taylor CT , Colgan SP . Regulation of immunity and inflammation by hypoxia in immunological niches. Nat Rev Immunol 2017; 17: 774- 85.

[48] Cantor JR , Abu-Remaileh M , Kanarek Net al. Physiologic medium rewires cellular metabolism and reveals uric acid as an endogenous inhibitor of UMP synthase. Cell 2017; 169: 258- 72.e17.

[49] Ma EH , Bantug G , Griss Tet al. Serine is an essential metabolite for effector T cell expansion. Cell Metab 2017; 25: 345- 57.

[50] Ma EH , Verway MJ , Johnson RMet al. Metabolic profiling using stable isotope tracing reveals distinct patterns of glucose utilization by physiologically activated CD8+ T cells. Immunity 2019; 51: 856- 70.e5.

[51] Sugiura A , Andrejeva G , Voss Ket al. MTHFD2 is a metabolic checkpoint controlling effector and T cell fate and function. Immunity 2022; 55: 65- 81.e9.

[52] Lee J , Walsh MC , Hoehn KLet al. Regulator of fatty acid metabolism, acetyl coenzyme a carboxylase 1, controls T cell immunity. J Immunol 2014; 192: 3190- 9.

[53] Ibitokou SA , Dillon BE , Sinha Met al. Early inhibition of fatty acid synthesis reduces generation of memory precursor effector T cells in chronic infection. J Immunol 2018; 200: 643- 56.

[54] Kidani Y , Elsaesser H , Hock MBet al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat Immunol 2013; 14: 489- 99.

[55] Zhu J , Thompson CB . Metabolic regulation of cell growth and proliferation. Nat Rev Mol Cell Biol 2019; 20: 436- 50.

[56] Lunt SY , Vander Heiden MG . Aerobic glycolysis:meeting the metabolic requirements of cell proliferation. Annu Rev Cell Dev Biol 2011; 27: 441- 64.

[57] Frauwirth KA , Riley JL , Harris MHet al. The CD28 signaling pathway regulates glucose metabolism. Immunity 2002; 16: 769- 77.

[58] Mittrücker HW , Kursar M , Köhler Aet al. Role of CD28 for the generation and expansion of antigen-specific CD8+ T lymphocytes during infection with Listeria monocytogenes. J Immunol 2001; 167: 5620- 7.

[59] Singh N , Chandler PR , Seki Yet al. Role of CD28 in fatal autoimmune disorder in scurfy mice. Blood 2007; 110: 1199- 206.

[60] Wellen KE , Thompson CB . A two-way street:reciprocal regulation of metabolism and signalling. Nat Rev Mol Cell Biol 2012; 13: 270- 6.

[61] Wellen KE , Hatzivassiliou G , Sachdeva UMet al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 2009; 324: 1076- 80.

[62] Roy DG , Chen J , Mamane Vet al. Methionine metabolism shapes T helper cell responses through regulation of epigenetic reprogramming. Cell Metab 2020; 31: 250- 66.e9.

[63] Ho PC , Bihuniak JD , Macintyre ANet al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 2015; 162: 1217- 28.

[64] Shi X , Bi Y , Yang Wet al. Ca2+ regulates T-cell receptor activation by modulating the charge property of lipids. Nature 2013; 493: 111- 5.

[65] Yang W , Bai Y , Xiong Yet al. Potentiating the antitumour response of CD8+ T cells by modulating cholesterol metabolism. Nature 2016; 531: 651- 5.

[66] Lim SA , Su W , Chapman NMet al. Lipid metabolism in T cell signaling and function. Nat Chem Biol 2022; 18: 470- 81.

[67] Josefowicz SZ , Lu LF , Rudensky AY . Regulatory T cells:mechanisms of differentiation and function. Annu Rev Immunol 2012; 30: 531- 64.

[68] Gerriets VA , Kishton RJ , Johnson MOet al. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat Immunol 2016; 17: 1459- 66.

[69] Ouyang W , Liao W , Luo CTet al. Novel Foxo1-dependent transcriptional programs control T-reg cell function. Nature 2012; 491: 554- 59.

[70] Beier UH , Angelin A , Akimova Tet al. Essential role of mitochondrial energy metabolism in Foxp3+ T-regulatory cell function and allograft survival. FASEB J 2015; 29: 2315- 26.

[71] Gerriets VA , Kishton RJ , Nichols AGet al. Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation. J Clin Investig 2015; 125: 194- 207.

[72] Lim SA , Wei J , Nguyen TMet al. Lipid signalling enforces functional specialization of Treg cells in tumours. Nature 2021; 591: 306- 11.

[73] Wang H , Franco F , Tsui YCet al. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat Immunol 2020; 21: 298- 308.

[74] Hori S , Nomura T , Sakaguchi S . Control of regulatory T cell development by the transcription factor Foxp3. Science 2003; 299: 1057- 61.

[75] Fontenot JD , Gavin MA , Rudensky AY . Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4: 330- 6.

[76] Weant AE , Michalek RD , Khan IUet al. Apoptosis regulators bim and fas function concurrently to control autoimmunity and CD8+ T cell contraction. Immunity 2008; 28: 218- 30.

[77] Hutcheson J , Scatizzi JC , Siddiqui AMet al. Combined deficiency of proapoptotic regulators Bim and Fas results in the early onset of systemic autoimmunity. Immunity 2008; 28: 206- 17.

[78] Hughes PD , Belz GT , Fortner KAet al. Apoptosis regulators Fas and Bim cooperate in shutdown of chronic immune responses and prevention of autoimmunity. Immunity 2008; 28: 197- 205.

[79] Kaech SM , Cui W . Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol 2012; 12: 749- 61.

[80] Jeannet G , Boudousquié C , Gardiol Net al. Essential role of the Wnt pathway effector Tcf-1 for the establishment of functional CD8 T cell memory. Proc Natl Acad Sci U S A 2010; 107: 9777- 82.

[81] Zhou X , Yu S , Zhao DMet al. Differentiation and persistence of memory CD8+ T cells depend on T cell factor 1. Immunity 2010; 33: 229- 40.

[82] Hess Michelini R , Doedens AL , Goldrath AWet al. Differentiation of CD8 memory T cells depends on Foxo1.J Exp Med 2013; 210: 1189- 200.

[83] Kim MV , Ouyang W , Liao Wet al. The transcription factor Foxo1 controls central-memory CD8+ T cell responses to infection. Immunity 2013; 39: 286- 97.

[84] Pearce EL , Walsh MC , Cejas PJet al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 2009; 460: 103- 7.

[85] van der Windt GJW , Everts B , Chang CHet al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 2012; 36: 68- 78.

[86] Pan Y , Tian T , Park COet al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 2017; 543: 252- 6.

[87] Cui GL , Staron MM , Gray SMet al. IL-7-induced glycerol transport and TAG synthesis promotes memory CD8+ T cell longevity. Cell 2015; 161: 750- 61.

[88] Wenes M , Jaccard A , Wyss Tet al. The mitochondrial pyruvate carrier regulates memory T cell differentiation and antitumor function. Cell Metab 2022; 34: 731- 46.e9.

[89] Sukumar M , Liu J , Ji Yet al. Inhibiting glycolytic metabolism enhances CD8+ T cell memory and antitumor function. J Clin Invest 2013; 123: 4479- 88.

[90] Phan AT , Doedens AL , Palazon Aet al. Constitutive glycolytic metabolism supports CD8+ T cell effector memory differentiation during viral infection. Immunity 2016; 45: 1024- 37.

[91] Pavlova NN , Zhu J , Thompson CB . The hallmarks of cancer metabolism:still emerging. Cell Metab 2022; 34: 355- 77.

[92] Hanahan D , Weinberg RA . Hallmarks of cancer:the next generation. Cell 2011; 144: 646- 74.

[93] Vander Heiden MG . Targeting cancer metabolism:a therapeutic window opens. Nat Rev Drug Discovery 2011; 10: 671- 84.

[94] Golub D , Iyengar N , Dogra Set al. Mutant isocitrate dehydrogenase inhibitors as targeted cancer therapeutics. Front Oncol 2019; 9: 417.

[95] Feng X , Zhang L , Xu Set al. ATP-citrate lyase (ACLY) in lipid metabolism and atherosclerosis:an updated review. Prog Lipid Res 2020; 77: 101006.

[96] Chang CH , Qiu J , O'Sullivan Det al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 2015; 162: 1229- 41.

[97] Reinfeld BI , Madden MZ , Wolf MMet al. Cell-programmed nutrient partitioning in the tumour microenvironment. Nature 2021; 593: 282- 8.

[98] Leone RD , Zhao L , Englert JMet al. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 2019; 366: 1013- 21.

[99] Nielsen J . Systems biology of metabolism. Annu Rev Biochem 2017; 86: 245- 75.

[100] Wang J , Alexander P , Wu Let al. Dependence of mouse embryonic stem cells on threonine catabolism. Science 2009; 325: 435- 9.

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