Mitochondrial Metabolism Regulation of T Cell–Mediated Immunity

Literature Cited

1. 1. 

   Buck MD, Sowell RT, Kaech SM, Pearce EL. 2017. Metabolic instruction of immunity. Cell 169:4570–86
   [Google Scholar]
2. 2. 

   O'Neill LAJ, Kishton RJ, Rathmell J. 2016. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16:9553–65
   [Google Scholar]
3. 3. 

   Mehta MM, Weinberg SE, Chandel NS. 2017. Mitochondrial control of immunity: beyond ATP. Nat. Rev. Immunol. 17:10608–20
   [Google Scholar]
4. 4. 

   Patel CH, Leone RD, Horton MR, Powell JD. 2019. Targeting metabolism to regulate immune responses in autoimmunity and cancer. Nat. Rev. Drug Discov. 18:9669–88
   [Google Scholar]
5. 5. 

   Warburg O, Wind F, Negelein E. 1927. The metabolism of tumors in the body. J. Gen. Physiol. 8:519–30
   [Google Scholar]
6. 6. 

   Warburg O. 1956. On the origin of cancer cells. Science 123:3191309–14 (from German)
   [Google Scholar]
7. 7. 

   Olenchock BA, Rathmell JC, Vander Heiden MG 2017. Biochemical underpinnings of immune cell metabolic phenotypes. Immunity 46:5703–13
   [Google Scholar]
8. 8. 

   Warburg O, Gawehn K, Geissler AW. 1958. [Metabolism of leukocytes]. Z. Naturforsch. B 13B:8515–16 (In German)
   [Google Scholar]
9. 9. 

   Koppenol WH, Bounds PL, Dang CV. 2011. Otto Warburg's contributions to current concepts of cancer metabolism. Nat. Rev. Cancer 11:5325–37
   [Google Scholar]
10. 10. 

    Leney-Greene MA, Boddapati AK, Su HC, Cantor JR, Lenardo MJ. 2020. Human plasma-like medium improves T lymphocyte activation. iScience 23:1100759
    [Google Scholar]
11. 11. 

    Cantor JR. 2019. The rise of physiologic media. Trends Cell Biol 29:11854–61
    [Google Scholar]
12. 12. 

    Hume DA, Radik JL, Ferber E, Weidemann MJ. 1978. Aerobic glycolysis and lymphocyte transformation. Biochem. J. 174:3703–9
    [Google Scholar]
13. 13. 

    Hume DA, Vijayakumar EK, Schweinberger F, Russell LM, Weidemann MJ. 1978. The role of calcium ions in the regulation of rat thymocyte pyruvate oxidation by mitogens. Biochem. J. 174:3711–16
    [Google Scholar]
14. 14. 

    Sena LA, Li S, Jairaman A, Prakriya M, Ezponda T et al. 2013. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity 38:2225–36
    [Google Scholar]
15. 15. 

    Tarasenko TN, Pacheco SE, Koenig MK, Gomez-Rodriguez J, Kapnick SM et al. 2017. Cytochrome c oxidase activity is a metabolic checkpoint that regulates cell fate decisions during T cell activation and differentiation. Cell Metab 25:61254–68.e7
    [Google Scholar]
16. 16. 

    Tan H, Yang K, Li Y, Shaw TI, Wang Y et al. 2017. Integrative proteomics and phosphoproteomics profiling reveals dynamic signaling networks and bioenergetics pathways underlying T cell activation. Immunity 46:3488–503
    [Google Scholar]
17. 17. 

    Buck MD, O'Sullivan D, Klein Geltink RI, Curtis JD, Chang C-H et al. 2016. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166:163–76
    [Google Scholar]
18. 18. 

    Weinberg SE, Singer BD, Steinert EM, Martinez CA, Mehta MM et al. 2019. Mitochondrial complex III is essential for suppressive function of regulatory T cells. Nature 565:7740495–99
    [Google Scholar]
19. 19. 

    Walker MA, Lareau CA, Ludwig LS, Karaa A, Sankaran VG et al. 2020. Purifying selection against pathogenic mitochondrial DNA in human T cells. N. Eng. J. Med. 383:1556–63
    [Google Scholar]
20. 20. 

    Ma EH, Verway MJ, Johnson RM, Roy DG, Steadman M et al. 2019. Metabolic profiling using stable isotope tracing reveals distinct patterns of glucose utilization by physiologically activated CD8⁺ T cells. Immunity 51:5856–70.e5
    [Google Scholar]
21. 21. 

    Chandel NS. 2015. Navigating Metabolism Cold Spring Harbor, NY: Cold Spring Harb. Lab.
22. 22. 

    Mullen AR, Wheaton WW, Jin ES, Chen P-H, Sullivan LB et al. 2011. Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481:7381385–88
    [Google Scholar]
23. 23. 

    Metallo CM, Gameiro PA, Bell EL, Mattaini KR, Yang J et al. 2011. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481:7381380–84
    [Google Scholar]
24. 24. 

    Martínez-Reyes I, Cardona LR, Kong H, Vasan K, McElroy GS et al. 2020. Mitochondrial ubiquinol oxidation is necessary for tumour growth. Nature 585:7824288–92
    [Google Scholar]
25. 25. 

    Wang R, Dillon CP, Shi LZ, Milasta S, Carter R et al. 2011. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35:6871–82
    [Google Scholar]
26. 26. 

    Vaeth M, Maus M, Klein-Hessling S, Freinkman E, Yang J et al. 2017. Store-operated Ca²⁺ entry controls clonal expansion of T cells through metabolic reprogramming. Immunity 47:4664–679.e6
    [Google Scholar]
27. 27. 

    Campbell SL, Wellen KE. 2018. Metabolic signaling to the nucleus in cancer. Mol. Cell 71:3398–408
    [Google Scholar]
28. 28. 

    Murphy MP. 2009. How mitochondria produce reactive oxygen species. Biochem. J. 417:11–13
    [Google Scholar]
29. 29. 

    Sanderson SM, Gao X, Dai Z, Locasale JW. 2019. Methionine metabolism in health and cancer: a nexus of diet and precision medicine. Nat. Rev. Cancer 19:11625–37
    [Google Scholar]
30. 30. 

    Islam MS, Leissing TM, Chowdhury R, Hopkinson RJ, Schofield CJ. 2018. 2-Oxoglutarate-dependent oxygenases. Annu. Rev. Biochem. 87:585–620
    [Google Scholar]
31. 31. 

    Intlekofer AM, Wang B, Liu H, Shah H, Carmona-Fontaine C et al. 2017. l-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH. Nat. Chem. Biol. 13:5494–500
    [Google Scholar]
32. 32. 

    Nadtochiy SM, Schafer X, Fu D, Nehrke K, Munger J, Brookes PS. 2016. Acidic pH is a metabolic switch for 2-hydroxyglutarate generation and signaling. J. Biol. Chem. 291:3820188–97
    [Google Scholar]
33. 33. 

    Oldham WM, Clish CB, Yang Y, Loscalzo J 2015. Hypoxia-mediated increases in l-2-hydroxyglutarate coordinate the metabolic response to reductive stress. Cell Metab 22:2291–303
    [Google Scholar]
34. 34. 

    Ansó E, Weinberg SE, Diebold LP, Thompson BJ, Malinge S et al. 2017. The mitochondrial respiratory chain is essential for haematopoietic stem cell function. Nat. Cell Biol. 19:6614–25
    [Google Scholar]
35. 35. 

    Mullen AR, Hu Z, Shi X, Jiang L, Boroughs LK et al. 2014. Oxidation of alpha-ketoglutarate is required for reductive carboxylation in cancer cells with mitochondrial defects. Cell Rep 7:51679–90
    [Google Scholar]
36. 36. 

    Intlekofer AM, Dematteo RG, Venneti S, Finley LWS, Lu C et al. 2015. Hypoxia induces production of L-2-hydroxyglutarate. Cell Metab 22:2304–11
    [Google Scholar]
37. 37. 

    West AP, Shadel GS. 2017. Mitochondrial DNA in innate immune responses and inflammatory pathology. Nat. Rev. Immunol. 17:6363–75
    [Google Scholar]
38. 38. 

    Palazon A, Goldrath AW, Nizet V, Johnson RS. 2014. HIF transcription factors, inflammation, and immunity. Immunity 41:4518–28
    [Google Scholar]
39. 39. 

    Lee P, Chandel NS, Simon MC. 2020. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat. Rev. Mol. Cell Biol. 21:5268–83
    [Google Scholar]
40. 40. 

    Chapman NM, Boothby MR, Chi H 2020. Metabolic coordination of T cell quiescence and activation. Nat. Rev. Immunol. 20:155–70
    [Google Scholar]
41. 41. 

    Cunningham CA, Bergsbaken T, Fink PJ. 2017. Cutting edge: Defective aerobic glycolysis defines the distinct effector function in antigen-activated CD8⁺ recent thymic emigrants. J. Immunol. 198:124575–80
    [Google Scholar]
42. 42. 

    Takada K, Jameson SC. 2009. Naive T cell homeostasis: from awareness of space to a sense of place. Nat. Rev. Immunol. 9:12823–32
    [Google Scholar]
43. 43. 

    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 6:3683–92
    [Google Scholar]
44. 44. 

    Macintyre AN, Gerriets VA, Nichols AG, Michalek RD, Rudolph MC et al. 2014. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab 20:161–72
    [Google Scholar]
45. 45. 

    Milasta S, Dillon CP, Sturm OE, Verbist KC, Brewer TL et al. 2016. Apoptosis-inducing-factor-dependent mitochondrial function is required for T cell but not B cell function. Immunity 44:188–102
    [Google Scholar]
46. 46. 

    Mendoza A, Fang V, Chen C, Serasinghe M, Verma A et al. 2017. Lymphatic endothelial S1P promotes mitochondrial function and survival in naive T cells. Nature 546:7656158–61
    [Google Scholar]
47. 47. 

    Chapman NM, Chi H 2018. Hallmarks of T-cell exit from quiescence. Cancer Immunol. Res. 6:5502–8
    [Google Scholar]
48. 48. 

    Mescher MF, Curtsinger JM, Agarwal P, Casey KA, Gerner M et al. 2006. Signals required for programming effector and memory development by CD8⁺ T cells. Immunol. Rev. 211:181–92
    [Google Scholar]
49. 49. 

    Makowski L, Chaib M, Rathmell JC. 2020. Immunometabolism: from basic mechanisms to translation. Immunol. Rev. 295:15–14
    [Google Scholar]
50. 50. 

    Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC et al. 2002. The CD28 signaling pathway regulates glucose metabolism. Immunity 16:6769–77
    [Google Scholar]
51. 51. 

    Ron-Harel N, Santos D, Ghergurovich JM, Sage PT, Reddy A et al. 2016. Mitochondrial biogenesis and proteome remodeling promote one-carbon metabolism for T cell activation. Cell Metab 24:1104–17
    [Google Scholar]
52. 52. 

    Quintana A, Schwindling C, Wenning AS, Becherer U, Rettig J et al. 2007. T cell activation requires mitochondrial translocation to the immunological synapse. PNAS 104:3614418–23
    [Google Scholar]
53. 53. 

    Menk AV, Scharping NE, Moreci RS, Zeng X, Guy C et al. 2018. Early TCR signaling induces rapid aerobic glycolysis enabling distinct acute T cell effector functions. Cell Rep 22:61509–21
    [Google Scholar]
54. 54. 

    Ho P-C, Bihuniak JD, Macintyre AN, Staron M, Liu X et al. 2015. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162:61217–28
    [Google Scholar]
55. 55. 

    Angiari S, Runtsch MC, Sutton CE, Palsson-McDermott EM, Kelly B et al. 2020. Pharmacological activation of pyruvate kinase M2 inhibits CD4⁺ T cell pathogenicity. Cell Metab. 31:2391–405
    [Google Scholar]
56. 56. 

    Chang C-H, Curtis JD, Maggi LB, Faubert B, Villarino AV et al. 2013. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153:61239–51
    [Google Scholar]
57. 57. 

    Yang Z, Shen Y, Oishi H, Matteson EL, Tian L et al. 2016. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci. Transl. Med. 8:331331ra38
    [Google Scholar]
58. 58. 

    Laniewski NG, Grayson JM. 2004. Antioxidant treatment reduces expansion and contraction of antigen-specific CD8⁺ T cells during primary but not secondary viral infection. J. Virol. 78:2011246–57
    [Google Scholar]
59. 59. 

    Kamiński MM, Sauer SW, Kamiński M, Opp S, Ruppert T et al. 2012. T cell activation is driven by an ADP-dependent glucokinase linking enhanced glycolysis with mitochondrial reactive oxygen species generation. Cell Rep 2:51300–15
    [Google Scholar]
60. 60. 

    Kaminski MM, Sauer SW, Klemke C-D, Süss D, Okun JG et al. 2010. Mitochondrial reactive oxygen species control T cell activation by regulating IL-2 and IL-4 expression: mechanism of ciprofloxacin-mediated immunosuppression. J. Immunol. 184:94827–41
    [Google Scholar]
61. 61. 

    Matsushita M, Freigang S, Schneider C, Conrad M, Bornkamm GW, Kopf M. 2015. T cell lipid peroxidation induces ferroptosis and prevents immunity to infection. J. Exp. Med. 212:4555–68
    [Google Scholar]
62. 62. 

    Case AJ, McGill JL, Tygrett LT, Shirasawa T, Spitz DR et al. 2011. Elevated mitochondrial superoxide disrupts normal T cell development, impairing adaptive immune responses to an influenza challenge. Free Radic. Biol. Med. 50:3448–58
    [Google Scholar]
63. 63. 

    Mak TW, Grusdat M, Duncan GS, Dostert C, Nonnenmacher Y et al. 2017. Glutathione primes T cell metabolism for inflammation. Immunity 46:4675–89
    [Google Scholar]
64. 64. 

    Siska PJ, Beckermann KE, Mason FM, Andrejeva G, Greenplate AR et al. 2017. Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma. JCI Insight 2:12e93411
    [Google Scholar]
65. 65. 

    Franchina DG, Dostert C, Brenner D. 2018. Reactive oxygen species: involvement in T cell signaling and metabolism. Trends Immunol 39:6489–502
    [Google Scholar]
66. 66. 

    Miyajima M, Zhang B, Sugiura Y, Sonomura K, Guerrini MM et al. 2017. Metabolic shift induced by systemic activation of T cells in PD-1-deficient mice perturbs brain monoamines and emotional behavior. Nat. Immunol. 18:121342–52
    [Google Scholar]
67. 67. 

    Ma EH, Bantug G, Griss T, Condotta S, Johnson RM et al. 2017. Serine is an essential metabolite for effector T cell expansion. Cell Metab 25:2345–57 Erratum. 2017. Cell Metab. 25(2):482
    [Google Scholar]
68. 68. 

    Gerriets VA, Kishton RJ, Nichols AG, Macintyre AN, Inoue M et al. 2015. Metabolic programming and PDHK1 control CD4⁺ T cell subsets and inflammation. J. Clin. Investig. 125:1194–207
    [Google Scholar]
69. 69. 

    Michalek RD, Gerriets VA, Jacobs SR, Macintyre AN, MacIver NJ et al. 2011. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4⁺ T cell subsets. J. Immunol. 186:63299–303
    [Google Scholar]
70. 70. 

    Tibbitt CA, Stark JM, Martens L, Ma J, Mold JE et al. 2019. Single-cell RNA sequencing of the T helper cell response to house dust mites defines a distinct gene expression signature in airway Th2 cells. Immunity 51:1169–84.e5
    [Google Scholar]
71. 71. 

    Dang EV, Barbi J, Yang H-Y, Jinasena D, Yu H et al. 2011. Control of T_H17/T_reg balance by hypoxia-inducible factor 1. Cell 146:5772–84
    [Google Scholar]
72. 72. 

    Shi LZ, Wang R, Huang G, Vogel P, Neale G et al. 2011. HIF1α-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of T_H17 and T_reg cells. J. Exp. Med. 208:71367–76
    [Google Scholar]
73. 73. 

    Jacobs SR, Herman CE, Maciver NJ, Wofford JA, Wieman HL et al. 2008. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J. Immunol. 180:74476–86
    [Google Scholar]
74. 74. 

    Yin Y, Choi S-C, Xu Z, Perry DJ, Seay H et al. 2015. Normalization of CD4⁺ T cell metabolism reverses lupus. Sci. Transl. Med. 7:274274ra18
    [Google Scholar]
75. 75. 

    Yin Y, Choi S-C, Xu Z, Zeumer L, Kanda N et al. 2016. Glucose oxidation is critical for CD4⁺ T cell activation in a mouse model of systemic lupus erythematosus. J. Immunol. 196:180–90
    [Google Scholar]
76. 76. 

    Titov AA, Baker HV, Brusko TM, Sobel ES, Morel L. 2019. Metformin inhibits the type 1 IFN response in human CD4⁺ T cells. J. Immunol. 203:2338–48
    [Google Scholar]
77. 77. 

    Franchi L, Monteleone I, Hao L-Y, Spahr MA, Zhao W et al. 2017. Inhibiting oxidative phosphorylation in vivo restrains Th17 effector responses and ameliorates murine colitis. J. Immunol. 198:72735–46
    [Google Scholar]
78. 78. 

    Kaufmann U, Kahlfuss S, Yang J, Ivanova E, Koralov SB, Feske S. 2019. Calcium signaling controls pathogenic Th17 cell-mediated inflammation by regulating mitochondrial function. Cell Metab 29:51104–18.e6
    [Google Scholar]
79. 79. 

    Kahlfuss S, Kaufmann U, Concepcion AR, Noyer L, Raphael D et al. 2020. STIM1-mediated calcium influx controls antifungal immunity and the metabolic function of non-pathogenic Th17 cells. EMBO Mol. Med. 12:8e11592
    [Google Scholar]
80. 80. 

    Lian G, Gnanaprakasam JR, Wang T, Wu R, Chen X et al. 2018. Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation. eLife 7:e36158
    [Google Scholar]
81. 81. 

    Matés JM, Campos-Sandoval JA, de Los Santos-Jiménez J, Márquez J. 2020. Glutaminases regulate glutathione and oxidative stress in cancer. Arch. Toxicol. 94:82603–23
    [Google Scholar]
82. 82. 

    Johnson MO, Wolf MM, Madden MZ, Andrejeva G, Sugiura A et al. 2018. Distinct regulation of Th17 and Th1 cell differentiation by glutaminase-dependent metabolism. Cell 175:71780–95.e19
    [Google Scholar]
83. 83. 

    Xu T, Stewart KM, Wang X, Liu K, Xie M et al. 2017. Metabolic control of T_H17 and induced T_reg cell balance by an epigenetic mechanism. Nature 548:7666228–33
    [Google Scholar]
84. 84. 

    Cronin SJF, Seehus C, Weidinger A, Talbot S, Reissig S et al. 2018. The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature 563:7732564–68
    [Google Scholar]
85. 85. 

    Desdín-Micó G, Soto-Heredero G, Aranda JF, Oller J, Carrasco E et al. 2020. T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science 368:64971371–76
    [Google Scholar]
86. 86. 

    Ekstrand MI, Falkenberg M, Rantanen A, Park CB, Gaspari M et al. 2004. Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum. Mol. Genet. 13:9935–44
    [Google Scholar]
87. 87. 

    Baixauli F, Acín-Pérez R, Villarroya-Beltrí C, Mazzeo C, Nuñez-Andrade N et al. 2015. Mitochondrial respiration controls lysosomal function during inflammatory T cell responses. Cell Metab 22:3485–98
    [Google Scholar]
88. 88. 

    Cantó C, Menzies KJ, Auwerx J. 2015. NAD⁺ metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab 22:131–53
    [Google Scholar]
89. 89. 

    Martínez-Reyes I, Chandel NS 2020. Mitochondrial TCA cycle metabolites control physiology and disease. Nat. Commun. 11:1102
    [Google Scholar]
90. 90. 

    Bailis W, Shyer JA, Zhao J, Canaveras JCG, Al Khazal FJ et al. 2019. Distinct modes of mitochondrial metabolism uncouple T cell differentiation and function. Nature 571:7765403–7
    [Google Scholar]
91. 91. 

    Peng M, Yin N, Chhangawala S, Xu K, Leslie CS, Li MO. 2016. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354:6311481–84
    [Google Scholar]
92. 92. 

    Hui S, Ghergurovich JM, Morscher RJ, Jang C, Teng X et al. 2017. Glucose feeds the TCA cycle via circulating lactate. Nature 551:7678115–18
    [Google Scholar]
93. 93. 

    Angelin A, Gil-de-Gómez L, Dahiya S, Jiao J, Guo L et al. 2017. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell Metab 25:61282–93.e7
    [Google Scholar]
94. 94. 

    Gerriets VA, Kishton RJ, Johnson MO, Cohen S, Siska PJ et al. 2016. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat. Immunol. 17:121459–66
    [Google Scholar]
95. 95. 

    Lee JH, Elly C, Park Y, Liu Y-C. 2015. E3 ubiquitin ligase VHL regulates hypoxia-inducible factor-1α to maintain regulatory T cell stability and suppressive capacity. Immunity 42:61062–74
    [Google Scholar]
96. 96. 

    Miska J, Lee-Chang C, Rashidi A, Muroski ME, Chang AL et al. 2019. HIF-1α is a metabolic switch between glycolytic-driven migration and oxidative phosphorylation-driven immunosuppression of Tregs in glioblastoma. Cell Rep 27:1226–37.e4
    [Google Scholar]
97. 97. 

    Beier UH, Angelin A, Akimova T, Wang L, Liu Y et al. 2015. Essential role of mitochondrial energy metabolism in Foxp3⁺ T-regulatory cell function and allograft survival. FASEB J 29:62315–26
    [Google Scholar]
98. 98. 

    Fu Z, Ye J, Dean JW, Bostick JW, Weinberg SE et al. 2019. Requirement of mitochondrial transcription factor A in tissue-resident regulatory T cell maintenance and function. Cell Rep 28:1159–71.e4
    [Google Scholar]
99. 99. 

    Kurniawan H, Franchina DG, Guerra L, Bonetti L, Soriano-Baguet L et al. 2020. Glutathione restricts serine metabolism to preserve regulatory T cell function. Cell Metab 31:5920–36.e7
    [Google Scholar]
100. 100. 

     Raud B, Roy DG, Divakaruni AS, Tarasenko TN, Franke R et al. 2018. Etomoxir actions on regulatory and memory T cells are independent of Cpt1a-mediated fatty acid oxidation. Cell Metab 28:3504–15.e7
     [Google Scholar]
101. 101. 

     Field CS, Baixauli F, Kyle RL, Puleston DJ, Cameron AM et al. 2020. Mitochondrial integrity regulated by lipid metabolism is a cell-intrinsic checkpoint for Treg suppressive function. Cell Metab 31:2422–37.e5
     [Google Scholar]
102. 102. 

     Li C, Spallanzani RG, Mathis D. 2020. Visceral adipose tissue Tregs and the cells that nurture them. Immunol. Rev. 295:1114–25
     [Google Scholar]
103. 103. 

     Cipolletta D, Feuerer M, Li A, Kamei N, Lee J et al. 2012. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486:7404549–53
     [Google Scholar]
104. 104. 

     Wang H, Franco F, Tsui Y-C, Xie X, Trefny MP et al. 2020. CD36-mediated metabolic adaptation supports regulatory T cell survival and function in tumors. Nat. Immunol. 21:3298–308
     [Google Scholar]
105. 105. 

     Kishton RJ, Sukumar M, Restifo NP. 2017. Metabolic regulation of T cell longevity and function in tumor immunotherapy. Cell Metab 26:194–109
     [Google Scholar]
106. 106. 

     Geltink RIK, Kyle RL, Pearce EL 2018. Unraveling the complex interplay between T cell metabolism and function. Annu. Rev. Immunol. 36:461–88
     [Google Scholar]
107. 107. 

     Sukumar M, Liu J, Ji Y, Subramanian M, Crompton JG et al. 2013. Inhibiting glycolytic metabolism enhances CD8⁺ T cell memory and antitumor function. J. Clin. Investig. 123:104479–88
     [Google Scholar]
108. 108. 

     Kawalekar OU, O'Connor RS, Fraietta JA, Guo L, McGettigan SE et al. 2016. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 44:2380–90
     [Google Scholar]
109. 109. 

     Cham CM, Gajewski TF. 2005. Glucose availability regulates IFN-γ production and p70S6 kinase activation in CD8⁺ effector T cells. J. Immunol. 174:84670–77
     [Google Scholar]
110. 110. 

     Cham CM, Driessens G, O'Keefe JP, Gajewski TF 2008. Glucose deprivation inhibits multiple key gene expression events and effector functions in CD8⁺ T cells. Eur. J. Immunol. 38:92438–50
     [Google Scholar]
111. 111. 

     Gubser PM, Bantug GR, Razik L, Fischer M, Dimeloe S et al. 2013. Rapid effector function of memory CD8⁺ T cells requires an immediate-early glycolytic switch. Nat. Immunol. 14:101064–72
     [Google Scholar]
112. 112. 

     Balmer ML, Ma EH, Bantug GR, Grählert J, Pfister S et al. 2016. Memory CD8⁺ T cells require increased concentrations of acetate induced by stress for optimal function. Immunity 44:61312–24
     [Google Scholar]
113. 113. 

     Bantug GR, Fischer M, Grählert J, Balmer ML, Unterstab G et al. 2018. Mitochondria-endoplasmic reticulum contact sites function as immunometabolic hubs that orchestrate the rapid recall response of memory CD8⁺ T cells. Immunity 48:3542–55.e6
     [Google Scholar]
114. 114. 

     Klarquist J, Chitrakar A, Pennock ND, Kilgore AM, Blain T et al. 2018. Clonal expansion of vaccine-elicited T cells is independent of aerobic glycolysis. Sci. Immunol. 3:27eaas9822
     [Google Scholar]
115. 115. 

     Sukumar M, Kishton RJ, Restifo NP. 2017. Metabolic reprograming of anti-tumor immunity. Curr. Opin. Immunol. 46:14–22
     [Google Scholar]
116. 116. 

     Sukumar M, Liu J, Mehta GU, Patel SJ, Roychoudhuri R et al. 2016. Mitochondrial membrane potential identifies cells with enhanced stemness for cellular therapy. Cell Metab 23:163–76
     [Google Scholar]
117. 117. 

     Ma R, Ji T, Zhang H, Dong W, Chen X et al. 2018. A Pck1-directed glycogen metabolic program regulates formation and maintenance of memory CD8⁺ T cells. Nat. Cell Biol. 20:121–27
     [Google Scholar]
118. 118. 

     van der Windt GJW, Everts B, Chang C-H, Curtis JD, Freitas TC et al. 2012. Mitochondrial respiratory capacity is a critical regulator of CD8⁺ T cell memory development. Immunity 36:168–78
     [Google Scholar]
119. 119. 

     van der Windt GJW, O'Sullivan D, Everts B, Huang SC-C, Buck MD et al. 2013. CD8 memory T cells have a bioenergetic advantage that underlies their rapid recall ability. PNAS 110:3514336–41
     [Google Scholar]
120. 120. 

     Quinn KM, Hussain T, Kraus F, Formosa LE, Lam WK et al. 2020. Metabolic characteristics of CD8⁺ T cell subsets in young and aged individuals are not predictive of functionality. Nat. Commun. 11:12857
     [Google Scholar]
121. 121. 

     Cui G, Staron MM, Gray SM, Ho P-C, Amezquita RA et al. 2015. IL-7-induced glycerol transport and TAG synthesis promotes memory CD8⁺ T cell longevity. Cell 161:4750–61
     [Google Scholar]
122. 122. 

     O'Sullivan D, van der Windt GJW, Huang SC-C, Curtis JD, Chang C-H et al. 2014. Memory CD8⁺ T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41:175–88
     [Google Scholar]
123. 123. 

     Divakaruni AS, Hsieh WY, Minarrieta L, Duong TN, Kim KKO et al. 2018. Etomoxir inhibits macrophage polarization by disrupting CoA homeostasis. Cell Metab 28:3490–503.e7
     [Google Scholar]
124. 124. 

     Pan Y, Tian T, Park CO, Lofftus SY, Mei S et al. 2017. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543:7644252–56
     [Google Scholar]
125. 125. 

     Tyrakis PA, Palazon A, Macias D, Lee KL, Phan AT et al. 2016. The immunometabolite S-2-hydroxyglutarate regulates CD8⁺ T-lymphocyte fate. Nature 540:7632236–41
     [Google Scholar]
126. 126. 

     Lim AR, Rathmell WK, Rathmell JC. 2020. The tumor microenvironment as a metabolic barrier to effector T cells and immunotherapy. eLife 9:e55185
     [Google Scholar]
127. 127. 

     O'Sullivan D, Sanin DE, Pearce EJ, Pearce EL 2019. Metabolic interventions in the immune response to cancer. Nat. Rev. Immunol. 19:5324–35
     [Google Scholar]
128. 128. 

     Vardhana SA, Hwee MA, Berisa M, Wells DK, Yost KE et al. 2020. Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen. Nat. Immunol. 21:91022–33
     [Google Scholar]
129. 129. 

     Chamoto K, Chowdhury PS, Kumar A, Sonomura K, Matsuda F et al. 2017. Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. PNAS 114:5E761–70
     [Google Scholar]
130. 130. 

     Scharping NE, Menk AV, Moreci RS, Whetstone RD, Dadey RE et al. 2016. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45:2374–88
     [Google Scholar]
131. 131. 

     Ogando J, Sáez ME, Santos J, Nuevo-Tapioles C, Gut M et al. 2019. PD-1 signaling affects cristae morphology and leads to mitochondrial dysfunction in human CD8⁺ T lymphocytes. J. Immunother. Cancer 7:1151
     [Google Scholar]
132. 132. 

     Thommen DS, Koelzer VH, Herzig P, Roller A, Trefny M et al. 2018. A transcriptionally and functionally distinct PD-1⁺ CD8⁺ T cell pool with predictive potential in non-small-cell lung cancer treated with PD-1 blockade. Nat. Med. 24:7994–1004
     [Google Scholar]
133. 133. 

     Kumar A, Chamoto K, Chowdhury PS, Honjo T. 2020. Tumors attenuating the mitochondrial activity in T cells escape from PD-1 blockade therapy. eLife 9:e52330
     [Google Scholar]
134. 134. 

     Chowdhury PS, Chamoto K, Kumar A, Honjo T. 2018. PPAR-induced fatty acid oxidation in T cells increases the number of tumor-reactive CD8⁺ T cells and facilitates anti-PD-1 therapy. Cancer Immunol. Res. 6:111375–87
     [Google Scholar]
135. 135. 

     Li C, Zhu B, Son YM, Wang Z, Jiang L et al. 2019. The transcription factor Bhlhe40 programs mitochondrial regulation of resident CD8⁺ T cell fitness and functionality. Immunity 51:3491–507.e7
     [Google Scholar]
136. 136. 

     Martí i Líndez A-A, Dunand-Sauthier I, Conti M, Gobet F, Núñez N et al. 2019. Mitochondrial arginase-2 is a cell-autonomous regulator of CD8⁺ T cell function and antitumor efficacy. JCI Insight 4:24e132975
     [Google Scholar]
137. 137. 

     Leone RD, Powell JD. 2020. Metabolism of immune cells in cancer. Nat. Rev. Cancer 20:9516–31
     [Google Scholar]
138. 138. 

     Wang W, Green M, Choi JE, Gijón M, Kennedy PD et al. 2019. CD8⁺ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569:7755270–74
     [Google Scholar]
139. 139. 

     Leone RD, Zhao L, Englert JM, Sun I-M, Oh M-H et al. 2019. Glutamine blockade induces divergent metabolic programs to overcome tumor immune evasion. Science 366:64681013–21
     [Google Scholar]
140. 140. 

     Oh M-H, Sun I-H, Zhao L, Leone RD, Sun I-M et al. 2020. Targeting glutamine metabolism enhances tumor-specific immunity by modulating suppressive myeloid cells. J. Clin. Investig. 130:73865–84
     [Google Scholar]