The spectrum of T cell metabolism in health and disease

Nature Reviews Immunology

Volumn 18, Issue 1, 2018, Pages 19-34

  Bantug, Glenn R ^a   Galluzzi, Lorenzo ^b,c   Kroemer, Guido ^{c,d,e,f,g,h,i}   Hess, Christoph ^a  

^a UNIVERSITY HOSPITAL BASEL   (Switzerland)

^b WEILL CORNELL MEDICAL COLLEGE   (United States)

^c UNIVERSITÉ PARIS DESCARTES   (France)

^d SORBONNE UNIVERSITÉ   (France)

^e CENTRE DE RECHERCHE DES CORDELIERS   (France)

^f INSERM   (France)

^g INSTITUT GUSTAVE ROUSSY   (France)

^h HÔPITAL EUROPÉEN GEORGES POMPIDOU   (France)

ⁱ KAROLINSKA UNIVERSITY HOSPITAL   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

AMINO ACID; ANTIGEN; COGNATE ANTIGEN; UNCLASSIFIED DRUG;

AUTOIMMUNITY; CELL METABOLISM; DIABETES MELLITUS; DISEASES; EFFECTOR CELL; GLYCOLYSIS; HEALTH; HOST; HUMAN; IMMUNOCOMPETENT CELL; INFECTION; INFLAMMATION; LIPID METABOLISM; LYMPH NODE; LYMPHOCYTE DIFFERENTIATION; LYMPHOCYTE FUNCTION; LYMPHOCYTE PROLIFERATION; MALIGNANT NEOPLASM; METABOLIC REPROGRAMMING; METABOLIC SYNDROME X; MICROENVIRONMENT; NONHUMAN; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION;

EID: 85039067207     PISSN: 14741733     EISSN: 14741741     Source Type: Journal    
DOI: 10.1038/nri.2017.99     Document Type: Review

References (240)

1. Suarez-Fueyo, A., Bradley, S. J. & Tsokos, G. C. T cells in systemic lupus erythematosus. Curr. Opin. Immunol. 43, 32-38 (2016).
2. Speiser, D. E., Ho, P. C. & Verdeil, G. Regulatory circuits of T cell function in cancer. Nat. Rev. Immunol. 16, 599-611 (2016).
3. McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205-2219 (2011).
4. Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486-499 (2015).
5. Sell, H., Habich, C. & Eckel, J. Adaptive immunity in obesity and insulin resistance. Nat. Rev. Endocrinol. 8, 709-716 (2012).
6. Wilson, C. B., Rowell, E. & Sekimata, M. Epigenetic control of T-helper-cell differentiation. Nat. Rev. Immunol. 9, 91-105 (2009).
7. + T-cell differentiation. Immunol. Rev. 261, 157-168 (2014).
8. MacIver, N. J., Michalek, R. D. & Rathmell, J. C. Metabolic regulation of T lymphocytes. Annu. Rev. Immunol. 31, 259-283 (2013).
9. Kinnaird, A., Zhao, S., Wellen, K. E. & Michelakis, E. D. Metabolic control of epigenetics in cancer. Nat. Rev. Cancer 16, 694-707 (2016).
10. Beisel, W. R. Metabolic response to infection. Annu. Rev. Med. 26, 9-20 (1975).
11. Beisel, W. R. Magnitude of the host nutritional responses to infection. Am. J. Clin. Nutr. 30, 1236-1247 (1977).
12. Wang, A. et al. Opposing effects of fasting metabolism on tissue tolerance in bacterial and viral inflammation. Cell 166, 1512-1525 (2016).
13. Gallin, J. I., Kaye, D. & O'Leary, W. M. Serum lipids in infection. N. Engl. J. Med. 281, 1081-1086 (1969).
14. McGuinness, O. P. Defective glucose homeostasis during infection. Annu. Rev. Nutr. 25, 9-35 (2005).
15. O'Neill, L. A., Kishton, R. J. & Rathmell, J. A guide to immunometabolism for immunologists. Nat. Rev. Immunol. 16, 553-565 (2016).
16. + T cell exhaustion. Immunity 45, 358-373 (2016).
17. Chi, H. Regulation and function of mTOR signalling in T cell fate decisions. Nat. Rev. Immunol. 12, 325-338 (2012).
18. Inoki, K., Zhu, T. & Guan, K. L. TSC2 mediates cellular energy response to control cell growth and survival. Cell 115, 577-590 (2003).
19. Manning, B. D. & Cantley, L. C. AKT/PKB signaling: navigating downstream. Cell 129, 1261-1274 (2007).
20. Delgoffe, G. M. et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12, 295-303 (2011).
21. + T cell differentiation. J. Clin. Invest. 125, 2090-2108 (2015).
22. + T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity 32, 67-78 (2010).
23. Ray, J. P. et al. The interleukin-2-mTORc1 kinase axis defines the signaling, differentiation, and metabolism of T helper 1 and follicular B helper T cells. Immunity 43, 690-702 (2015).
24. Yang, K. et al. T cell exit from quiescence and differentiation into Th2 cells depend on Raptor-mTORC1-mediated metabolic reprogramming. Immunity 39, 1043-1056 (2013).
25. Zeng, H. et al. mTORC1 and mTORC2 kinase signaling and glucose metabolism drive follicular helper T cell differentiation. Immunity 45, 540-554 (2016).
26. Finlay, D. & Cantrell, D. A. Metabolism, migration and memory in cytotoxic T cells. Nat. Rev. Immunol. 11, 109-117 (2011).
27. Wang, R. et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 35, 871-882 (2011).
28. + T cells. Nat. Immunol. 15, 884-893 (2014).
29. + T cell response to infection and memory T cell formation. Nat. Immunol. 14, 404-412 (2013).
30. + T cells to persistent antigen. Nat. Immunol. 14, 1173-1182 (2013).
31. Macintyre, A. N. et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 20, 61-72 (2014).
32. Jacobs, S. R. et al. Glucose uptake is limiting in T cell activation and requires CD28-mediated Akt-dependent and independent pathways. J. Immunol. 180, 4476-4486 (2008).
33. Maciver, N. J. et al. Glucose metabolism in lymphocytes is a regulated process with significant effects on immune cell function and survival. J. Leukoc. Biol. 84, 949-957 (2008).
34. Cretenet, G. et al. Cell surface Glut1 levels distinguish human CD4 and CD8 T lymphocyte subsets with distinct effector functions. Sci. Rep. 6, 24129 (2016).
35. Schurich, A. et al. Distinct metabolic requirements of exhausted and functional virus-specific CD8 T cells in the same host. Cell Rep. 16, 1243-1252 (2016).
36. Man, K. et al. The transcription factor IRF4 is essential for TCR affinity-mediated metabolic programming and clonal expansion of T cells. Nat. Immunol. 14, 1155-1165 (2013).
37. + T cell formation. eLife http://dx.doi.org/10.7554/eLife.03706 (2014).
38. + T cell memory and antitumor function. J. Clin. Invest. 123, 4479-4488 (2013).
39. + T cell subsets. J. Immunol. 186, 3299-3303 (2011).
40. reg cells. J. Exp. Med. 208, 1367-1376 (2011).
41. reg balance by hypoxia-inducible factor 1. Cell 146, 772-784 (2011).
42. Shehade, H., Acolty, V., Moser, M. & Oldenhove, G. Cutting edge: hypoxia-inducible factor 1 negatively regulates Th1 function. J. Immunol. 195, 1372-1376 (2015).
43. H2 cell differentiation and allergic airway inflammation. J. Allergy Clin. Immunol. 137, 231-245 (2016).
44. Corre, I., Gomez, M., Vielkind, S. & Cantrell, D. A. Analysis of thymocyte development reveals that the GTPase RhoA is a positive regulator of T cell receptor responses in vivo. J. Exp. Med. 194, 903-914 (2001).
45. Saoudi, A., Kassem, S., Dejean, A. & Gaud, G. Rho-GTPases as key regulators of T lymphocyte biology. Small GTPases 5, e28208 (2014).
46. Singleton, K. L. et al. Spatiotemporal patterning during T cell activation is highly diverse. Sci. Signal 2, ra15 (2009).
47. Verbist, K. C. et al. Metabolic maintenance of cell asymmetry following division in activated T lymphocytes. Nature 532, 389-393 (2016).
48. Jacinto, E. et al. Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive. Nat. Cell Biol. 6, 1122-1128 (2004).
49. + T cells. Eur. J. Immunol. 38, 2438-2450 (2008).
50. + effector T cells. J. Immunol. 174, 4670-4677 (2005).
51. Chang, C. H. et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 153, 1239-1251 (2013).
52. + T cells requires an immediate-early glycolytic switch. Nat. Immunol. 14, 1064-1072 (2013).
53. Peng, M. et al. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 354, 481-484 (2016).
54. Blagih, J. et al. The energy sensor AMPK regulates T cell metabolic adaptation and effector responses in vivo. Immunity 42, 41-54 (2015).
55. Altman, B. J., Stine, Z. E. & Dang, C. V. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat. Rev. Cancer 16, 619-634 (2016).
56. Metallo, C. M. et al. Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia. Nature 481, 380-384 (2011).
57. Sinclair, L. V. et al. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat. Immunol. 14, 500-508 (2013).
58. Wolfson, R. L. et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science 351, 43-48 (2016).
59. Locasale, J. W. Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat. Rev. Cancer 13, 572-583 (2013).
60. Ma, E. H. et al. Serine is an essential metabolite for effector T cell expansion. Cell Metab. 25, 345-357 (2017).
61. + T cell differentiation. Ann. NY Acad. Sci. 1183, 251-266 (2010).
62. Pearce, E. L. et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460, 103-107 (2009).
63. Araki, K. et al. mTOR regulates memory CD8 T-cell differentiation. Nature 460, 108-112 (2009).
64. Hardie, D. G. AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer. Biochem. Soc. Trans. 39, 1-13 (2011).
65. + T cell memory development. Immunity 36, 68-78 (2012).
66. Buck, M. D. et al. Mitochondrial dynamics controls T cell fate through metabolic programming. Cell 166, 63-76 (2016).
67. + T cells use cell-intrinsic lipolysis to support the metabolic programming necessary for development. Immunity 41, 75-88 (2014).
68. + T cell longevity. Cell 161, 750-761 (2015).
69. Jameson, S. C. & Masopust, D. Diversity in T cell memory: an embarrassment of riches. Immunity 31, 859-871 (2009).
70. Wherry, E. J., Blattman, J. N., Murali-Krishna, K., van der Most, R. & Ahmed, R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J. Virol. 77, 4911-4927 (2003).
71. Wherry, E. J. et al. Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4, 225-234 (2003).
72. + T cell effector memory differentiation during viral infection. Immunity 45, 1024-1037 (2016).
73. + central memory T cells. Immunity 41, 116-126 (2014).
74. Xu, Y. et al. Glycolysis determines dichotomous regulation of T cell subsets in hypoxia. J. Clin. Invest. 126, 2678-2688 (2016).
75. + T cell function under hypoxic conditions. J. Immunol. 196, 106-114 (2016).
76. Mueller, S. N. & Mackay, L. K. Tissue-resident memory T cells: local specialists in immune defence. Nat. Rev. Immunol. 16, 79-89 (2016).
77. Pan, Y. et al. Survival of tissue-resident memory T cells requires exogenous lipid uptake and metabolism. Nature 543, 252-256 (2017).
78. + T cells require increased concentrations of acetate induced by stress for optimal function. Immunity 44, 1312-1324 (2016).
79. Hotamisligil, G. S. Inflammation, metaflammation and immunometabolic disorders. Nature 542, 177-185 (2017).
80. Donath, M. Y. & Shoelson, S. E. Type 2 diabetes as an inflammatory disease. Nat. Rev. Immunol. 11, 98-107 (2011).
81. Feuerer, M. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat. Med. 15, 930-939 (2009).
82. Winer, D. A., Winer, S., Chng, M. H., Shen, L. & Engleman, E. G. B lymphocytes in obesity-related adipose tissue inflammation and insulin resistance. Cell. Mol. Life Sci. 71, 1033-1043 (2014).
83. Winer, S. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat. Med. 15, 921-929 (2009).
84. + effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nat. Med. 15, 914-920 (2009).
85. Zuniga, L. A. et al. IL-17 regulates adipogenesis, glucose homeostasis, and obesity. J. Immunol. 185, 6947-6959 (2010).
86. McLaughlin, T. et al. T-Cell profile in adipose tissue is associated with insulin resistance and systemic inflammation in humans. Arterioscler Thromb. Vasc. Biol. 34, 2637-2643 (2014).
87. Yang, H. et al. Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance. J. Immunol. 185, 1836-1845 (2010).
88. Lynch, L. Adipose invariant natural killer T cells. Immunology 142, 337-346 (2014).
89. Haversen, L., Danielsson, K. N., Fogelstrand, L. & Wiklund, O. Induction of proinflammatory cytokines by long-chain saturated fatty acids in human macrophages. Atherosclerosis 202, 382-393 (2009).
90. Martinez, N. et al. Chromatin decondensation and T cell hyperresponsiveness in diabetes-associated hyperglycemia. J. Immunol. 193, 4457-4468 (2014).
91. Stentz, F. B. & Kitabchi, A. E. Hyperglycemia-induced activation of human T-lymphocytes with de novo emergence of insulin receptors and generation of reactive oxygen species. Biochem. Biophys. Res. Commun. 335, 491-495 (2005).
92. Chen, S. et al. Transcriptional coactivator p300 regulates glucose-induced gene expression in endothelial cells. Am. J. Physiol. Endocrinol. Metab. 298, E127-E137 (2010).
93. Deb, D. K., Chen, Y., Sun, J., Wang, Y. & Li, Y. C. ATP-citrate lyase is essential for high glucose-induced histone hyperacetylation and fibrogenic gene up-regulation in mesangial cells. Am. J. Physiol. Renal Physiol. 313, F423-F429 (2017).
94. Mortuza, R., Chen, S., Feng, B., Sen, S. & Chakrabarti, S. High glucose induced alteration of SIRTs in endothelial cells causes rapid aging in a p300 and FOXO regulated pathway. PLoS ONE 8, e54514 (2013).
95. Garcia-Jimenez, C., Garcia-Martinez, J. M., Chocarro-Calvo, A. & De la Vieja, A. A new link between diabetes and cancer: enhanced WNT/ß-catenin signaling by high glucose. J. Mol. Endocrinol. 52, R51-R66 (2014).
96. Accili, D. & Arden, K. C. FoxOs at the crossroads of cellular metabolism, differentiation, and transformation. Cell 117, 421-426 (2004).
97. Mitro, N. et al. The nuclear receptor LXR is a glucose sensor. Nature 445, 219-223 (2007).
98. Salt, I. P., Johnson, G., Ashcroft, S. J. & Hardie, D. G. AMP-activated protein kinase is activated by low glucose in cell lines derived from pancreatic beta cells, and may regulate insulin release. Biochem. J. 335, 533-539 (1998).
99. Bensinger, S. J. et al. LXR signaling couples sterol metabolism to proliferation in the acquired immune response. Cell 134, 97-111 (2008).
100. Fabre, S. et al. Stable activation of phosphatidylinositol 3-kinase in the T cell immunological synapse stimulates Akt signaling to FoxO1 nuclear exclusion and cell growth control. J. Immunol. 174, 4161-4171 (2005).
101. + memory stem cells. Nat. Med. 15, 808-813 (2009).
102. Kennedy, A., Martinez, K., Chuang, C. C., LaPoint, K. & McIntosh, M. Saturated fatty acid-mediated inflammation and insulin resistance in adipose tissue: mechanisms of action and implications. J. Nutr. 139, 1-4 (2009).
103. Pal, D. et al. Fetuin-A acts as an endogenous ligand of TLR4 to promote lipid-induced insulin resistance. Nat. Med. 18, 1279-1285 (2012).
104. Eguchi, K. et al. Saturated fatty acid and TLR signaling link beta cell dysfunction and islet inflammation. Cell Metab. 15, 518-533 (2012).
105. Haghikia, A. et al. Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity 43, 817-829 (2015).
106. Endo, Y. et al. Obesity drives Th17 cell differentiation by inducing the lipid metabolic kinase. ACC1. Cell Rep. 12, 1042-1055 (2015).
107. + T cell differentiation via PI3K p110δ-Akt-mediated signals. Cell Metab. 25, 593-609 (2017).
108. Duhen, T., Geiger, R., Jarrossay, D., Lanzavecchia, A. & Sallusto, F. Production of interleukin 22 but not interleukin 17 by a subset of human skin-homing memory T cells. Nat. Immunol. 10, 857-863 (2009).
109. H17 cells produce IFN-γ or IL-10 and are regulated by IL-1ß. Nature 484, 514-518 (2012).
110. + T cells regulates TCR activation and experimental colitis in mice. J. Clin. Invest. 120, 570-581 (2010).
111. Reynolds, J. M., Martinez, G. J., Chung, Y. & Dong, C. Toll-like receptor 4 signaling in T cells promotes autoimmune inflammation. Proc. Natl Acad. Sci. USA 109, 13064-13069 (2012).
112. H17 differentiation by generating endogenous RORγ agonists. Nat. Chem. Biol. 11, 141-147 (2015).
113. Santori, F. R. et al. Identification of natural RORγ ligands that regulate the development of lymphoid cells. Cell Metab. 21, 286-297 (2015).
114. Soroosh, P. et al. Oxysterols are agonist ligands of RORγt and drive Th17 cell differentiation. Proc. Natl Acad. Sci. USA 111, 12163-12168 (2014).
115. Wang, C. et al. CD5L/AIM regulates lipid biosynthesis and restrains Th17 cell pathogenicity. Cell 163, 1413-1427 (2015).
116. Angela, M. et al. Fatty acid metabolic reprogramming via mTOR-mediated inductions of PPARgamma directs early activation of T cells. Nat. Commun. 7, 13683 (2016).
117. Kidani, Y. et al. Sterol regulatory element-binding proteins are essential for the metabolic programming of effector T cells and adaptive immunity. Nat. Immunol. 14, 489-499 (2013).
118. Fessler, M. B. The intracellular cholesterol landscape: dynamic integrator of the immune response. Trends Immunol. 37, 819-830 (2016).
119. Anghel, S. I. & Wahli, W. Fat poetry: a kingdom for PPARγ. Cell Res. 17, 486-511 (2007).
120. Clark, R. B. et al. The nuclear receptor PPARγ and immunoregulation: PPARγ mediates inhibition of helper T cell responses. J. Immunol. 164, 1364-1371 (2000).
121. Cunard, R. et al. Repression of IFN-γ expression by peroxisome proliferator-activated receptor γ. J. Immunol. 172, 7530-7536 (2004).
122. Yang, X. Y. et al. Activation of human T lymphocytes is inhibited by peroxisome proliferator-activated receptor gamma (PPARγ) agonists. PPARγ co-association with transcription factor NFAT. J. Biol. Chem. 275, 4541-4544 (2000).
123. Cipolletta, D. et al. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature 486, 549-553 (2012).
124. Choi, J. M. & Bothwell, A. L. The nuclear receptor PPARs as important regulators of T-cell functions and autoimmune diseases. Mol. Cells 33, 217-222 (2012).
125. Abraham, C. & Cho, J. H. Inflammatory bowel disease. N. Engl. J. Med. 361, 2066-2078 (2009).
126. Dendrou, C. A., Fugger, L. & Friese, M. A. Immunopathology of multiple sclerosis. Nat. Rev. Immunol. 15, 545-558 (2015).
127. Deng, Y., Chang, C. & Lu, Q. The inflammatory response in psoriasis: a comprehensive review. Clin. Rev. Allergy Immunol. 50, 377-389 (2016).
128. Chung, Y. et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 30, 576-587 (2009).
129. H17 cells in the absence of TGF-ß signalling. Nature 467, 967-971 (2010).
130. H17 cells. Nat. Immunol. 18, 74-85 (2017).
131. Jain, R. et al. Interleukin-23-Induced transcription factor blimp-1 promotes pathogenicity of T helper 17 cells. Immunity 44, 131-142 (2016).
132. H17 cells. Nat. Immunol. 13, 991-999 (2012).
133. Mailer, R. K. et al. IL-1ß promotes Th17 differentiation by inducing alternative splicing of FOXP3. Sci. Rep. 5, 14674 (2015).
134. H17 axis determines the onset of autoimmune disease. Nat. Immunol. 18, 104-113 (2017).
135. Guma, M., Tiziani, S. & Firestein, G. S. Metabolomics in rheumatic diseases: desperately seeking biomarkers. Nat. Rev. Rheumatol 12, 269-281 (2016).
136. Piotrowski, J. T., Gomez, T. S., Schoon, R. A., Mangalam, A. K. & Billadeau, D. D. WASH knockout T cells demonstrate defective receptor trafficking, proliferation, and effector function. Mol. Cell. Biol. 33, 958-973 (2013).
137. + T cell metabolism reverses lupus. Sci. Transl. Med. 7, 274ra18 (2015).
138. Li, P., Yin, Y. L., Li, D., Kim, S. W. & Wu, G. Amino acids and immune function. Br. J. Nutr. 98, 237-252 (2007).
139. Wannemacher, R. W. Jr., Powanda, M. C. & Dinterman, R. E. Amino acid flux and protein synthesis after exposure of rats to either Diplococcus pneumoniae or Salmonella typhimurium. Infect. Immun. 10, 60-65 (1974).
140. Kolev, M. et al. Complement regulates nutrient influx and metabolic reprogramming during Th1 cell responses. Immunity 42, 1033-1047 (2015).
141. H17 cell differentiation by activating the amino acid starvation response. Science 324, 1334-1338 (2009).
142. Keller, T. L. et al. Halofuginone and other febrifugine derivatives inhibit prolyl-tRNA synthetase. Nat. Chem. Biol. 8, 311-317 (2012).
143. Newgard, C. B. Interplay between lipids and branched-chain amino acids in development of insulin resistance. Cell Metab. 15, 606-614 (2012).
144. + T cells. J. Biol. Chem. 289, 18793-18804 (2014).
145. Carr, E. L. et al. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J. Immunol. 185, 1037-1044 (2010).
146. Raposo, B., Vaartjes, D., Ahlqvist, E., Nandakumar, K. S. & Holmdahl, R. System A amino acid transporters regulate glutamine uptake and attenuate antibody-mediated arthritis. Immunology 146, 607-617 (2015).
147. Klysz, D. et al. Glutamine-dependent alpha-ketoglutarate production regulates the balance between T helper 1 cell and regulatory T cell generation. Sci. Signal 8, ra97 (2015).
148. Nakaya, M. et al. Inflammatory T cell responses rely on amino acid transporter ASCT2 facilitation of glutamine uptake and mTORC1 kinase activation. Immunity 40, 692-705 (2014).
149. Ron-Harel, N. et al. Mitochondrial biogenesis and proteome remodeling promote one-carbon metabolism for T cell activation. Cell Metab. 24, 104-117 (2016).
150. Huennekens, F. M. The methotrexate story: a paradigm for development of cancer chemotherapeutic agents. Adv. Enzyme Regul. 34, 397-419 (1994).
151. Bauerle, M. R., Schwalm, E. L. & Booker, S. J. Mechanistic diversity of radical S-adenosylmethionine (SAM)-dependent methylation. J. Biol. Chem. 290, 3995-4002 (2015).
152. Berod, L. et al. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat. Med. 20, 1327-1333 (2014).
153. Mangalam, A. et al. Profile of circulatory metabolites in a relapsing-remitting animal model of multiple sclerosis using global metabolomics. J. Clin. Cell Immunol. http://dx.doi.org/10.4172/2155-9899.1000150 (2013).
154. Bhargava, P. & Calabresi, P. A. Metabolomics in multiple sclerosis. Mult. Scler. 22, 451-460 (2016).
155. Youssef, S. et al. The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420, 78-84 (2002).
156. + T cells derived from patients with multiple sclerosis. J. Immunol. 187, 3431-3437 (2011).
157. Smyth, M. J., Ngiow, S. F., Ribas, A. & Teng, M. W. Combination cancer immunotherapies tailored to the tumour microenvironment. Nat. Rev. Clin. Oncol. 13, 143-158 (2016).
158. Gottfried, E., Kreutz, M. & Mackensen, A. Tumor metabolism as modulator of immune response and tumor progression. Semin. Cancer Biol. 22, 335-341 (2012).
159. Siska, P. J. & Rathmell, J. C. T cell metabolic fitness in antitumor immunity. Trends Immunol. 36, 257-264 (2015).
160. Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229-1241 (2015).
161. Ho, P. C. et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217-1228 (2015).
162. Scharping, N. E. et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45, 374-388 (2016).
163. Ackerman, D. & Simon, M. C. Hypoxia, lipids, and cancer: surviving the harsh tumor microenvironment. Trends Cell Biol. 24, 472-478 (2014).
164. Galluzzi, L., Kepp, O., Vander Heiden, M. G. & Kroemer, G. Metabolic targets for cancer therapy. Nat. Rev. Drug Discov. 12, 829-846 (2013).
165. Salazar-Roa, M. & Malumbres, M. Fueling the cell division cycle. Trends Cell Biol. 27, 69-81 (2017).
166. + T-cell responses and vaccine-induced tumor eradication. Cancer Res. 75, 3279-3291 (2015).
167. Pollizzi, K. N. & Powell, J. D. Regulation of T cells by mTOR: the known knowns and the known unknowns. Trends Immunol. 36, 13-20 (2015).
168. Geiger, R. et al. L-Arginine modulates T cell metabolism and enhances survival and anti-tumor activity. Cell 167, 829-842 (2016).
169. Jain, M. et al. Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336, 1040-1044 (2012).
170. + T cells by modulating cholesterol metabolism. Nature 531, 651-655 (2016).
171. Comerford, S. A. et al. Acetate dependence of tumors. Cell 159, 1591-1602 (2014).
172. Telang, S. et al. Small molecule inhibition of 6-phosphofructo-2-kinase suppresses t cell activation. J. Transl Med. 10, 95 (2012).
173. Carracedo, A., Cantley, L. C. & Pandolfi, P. P. Cancer metabolism: fatty acid oxidation in the limelight. Nat. Rev. Cancer 13, 227-232 (2013).
174. Zhao, E. et al. Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat. Immunol. 17, 95-103 (2016).
175. Gerriets, V. A. et al. Foxp3 and Toll-like receptor signaling balance Treg cell anabolic metabolism for suppression. Nat. Immunol. 17, 1459-1466 (2016).
176. + T cells inhibit antitumor immune memory modulated by mTOR inhibition. Cancer Res. 74, 2217-2228 (2014).
177. Mineharu, Y., Kamran, N., Lowenstein, P. R. & Castro, M. G. Blockade of mTOR signaling via rapamycin combined with immunotherapy augments antiglioma cytotoxic and memory T-cell functions. Mol. Cancer Ther. 13, 3024-3036 (2014).
178. + T cell priming to promote memory formation and metabolic readiness. J. Immunol. 194, 2089-2098 (2015).
179. Li, Y. et al. Persistent antigen and prolonged AKT-mTORC1 activation underlie memory CD8 T cell impairment in the absence of CD4 T cells. J. Immunol. 195, 1591-1598 (2015).
180. + T cells with augmented ability to generate long-lasting memory cells. PLoS ONE 6, e20107 (2011).
181. + T cell survival and memory formation. Nat. Immunol. 15, 1152-1161 (2014).
182. Wei, J. et al. Autophagy enforces functional integrity of regulatory T cells by coupling environmental cues and metabolic homeostasis. Nat. Immunol. 17, 277-285 (2016).
183. Clever, D. et al. Oxygen sensing by T cells establishes an immunologically tolerant metastatic niche. Cell 166, 1117-1131 (2016).
184. Hatfield, S. M. et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci. Transl. Med. 7, 277ra30 (2015).
185. Ohashi, T. et al. Dichloroacetate improves immune dysfunction caused by tumor-secreted lactic acid and increases antitumor immunoreactivity. Int. J. Cancer 133, 1107-1118 (2013).
186. Pilon-Thomas, S. et al. Neutralization of tumor acidity improves antitumor responses to immunotherapy. Cancer Res. 76, 1381-1390 (2016).
187. Calcinotto, A. et al. Modulation of microenvironment acidity reverses anergy in human and murine tumor-infiltrating T lymphocytes. Cancer Res. 72, 2746-2756 (2012).
188. Patsoukis, N. et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat. Commun. 6, 6692 (2015).
189. Eil, R. et al. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537, 539-543 (2016).
190. + T cells. PLoS ONE 9, e99432 (2014).
191. Huang, Q. et al. Caspase 3-mediated stimulation of tumor cell repopulation during cancer radiotherapy. Nat. Med. 17, 860-866 (2011).
192. Wang, Y. et al. Uric acid enhances the antitumor immunity of dendritic cell-based vaccine. Sci. Rep. 5, 16427 (2015).
193. Pietrocola, F. et al. Caloric restriction mimetics enhance anticancer immunosurveillance. Cancer Cell 30, 147-160 (2016).
194. Ohta, A. A. Metabolic immune checkpoint: adenosine in tumor microenvironment. Front. Immunol. 7, 109 (2016).
195. Galluzzi, L., Bravo-San Pedro, J. M., Demaria, S., Formenti, S. C. & Kroemer, G. Activating autophagy to potentiate immunogenic chemotherapy and radiation therapy. Nat. Rev. Clin. Oncol. 14, 247-258 (2017).
196. Rao, S. et al. A dual role for autophagy in a murine model of lung cancer. Nat. Commun. 5, 3056 (2014).
197. Fletcher, M. et al. l-Arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells. Cancer Res. 75, 275-283 (2015).
198. Ravishankar, B. et al. The amino acid sensor GCN2 inhibits inflammatory responses to apoptotic cells promoting tolerance and suppressing systemic autoimmunity. Proc. Natl Acad. Sci. USA 112, 10774-10779 (2015).
199. Nowak, E. C. et al. Tryptophan hydroxylase-1 regulates immune tolerance and inflammation. J. Exp. Med. 209, 2127-2135 (2012).
200. Buque, A. et al. Trial Watch-Small molecules targeting the immunological tumor microenvironment for cancer therapy. Oncoimmunology 5, e1149674 (2016).
201. + T cell dysfunction in tumor-bearing mice. J. Immunol. 190, 812-820 (2013).
202. Kawalekar, O. U. et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 44, 380-390 (2016).
203. Angelini, G. et al. Antigen-presenting dendritic cells provide the reducing extracellular microenvironment required for T lymphocyte activation. Proc. Natl Acad. Sci. USA 99, 1491-1496 (2002).
204. Al-Herz, W. et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front. Immunol. 5, 162 (2014).
205. Fodil, N., Langlais, D. & Gros, P. Primary immunodeficiencies and inflammatory disease: a growing genetic intersection. Trends Immunol. 37, 126-140 (2016).
206. Angulo, I. et al. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science 342, 866-871 (2013).
207. Lucas, C. L. et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency. Nat. Immunol. 15, 88-97 (2014).
208. Galluzzi, L. et al. Molecular definitions of autophagy and related processes. EMBO J. 36, 1811-1836 (2017).
209. Green, D. R., Galluzzi, L. & Kroemer, G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333, 1109-1112 (2011).
210. Menzies, F. M., Fleming, A. & Rubinsztein, D. C. Compromised autophagy and neurodegenerative diseases. Nat. Rev. Neurosci. 16, 345-357 (2015).
211. Galluzzi, L., Bravo-San Pedro, J. M., Levine, B., Green, D. R. & Kroemer, G. Pharmacological modulation of autophagy: therapeutic potential and persisting obstacles. Nat. Rev. Drug Discov. 16, 487-511 (2017).
212. Galluzzi, L., Pietrocola, F., Levine, B. & Kroemer, G. Metabolic control of autophagy. Cell 159, 1263-1276 (2014).
213. Kaur, J. & Debnath, J. Autophagy at the crossroads of catabolism and anabolism. Nat. Rev. Mol. Cell Biol. 16, 461-472 (2015).
214. He, C. et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511-515 (2012).
215. Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573-1577 (2011).
216. Deretic, V., Saitoh, T. & Akira, S. Autophagy in infection, inflammation and immunity. Nat. Rev. Immunol. 13, 722-737 (2013).
217. Nakagawa, I. et al. Autophagy defends cells against invading group A Streptococcus. Science 306, 1037-1040 (2004).
218. Galluzzi, L. et al. Autophagy in malignant transformation and cancer progression. EMBO J. 34, 856-880 (2015).
219. Nakahira, K. et al. Autophagy proteins regulate innate immune responses by inhibiting the release of mitochondrial DNA mediated by the NALP3 inflammasome. Nat. Immunol. 12, 222-230 (2011).
220. Li, Y. et al. Efficient cross-presentation depends on autophagy in tumor cells. Cancer Res. 68, 6889-6895 (2008).
221. Yecies, J. L. & Manning, B. D. Transcriptional control of cellular metabolism by mTOR signaling. Cancer Res. 71, 2815-2820 (2011).
222. Mahnke, J. et al. Interferon Regulatory Factor 4 controls TH1 cell effector function and metabolism. Sci. Rep. 6, 35521 (2016).
223. Oestreich, K. J. et al. Bcl-6 directly represses the gene program of the glycolysis pathway. Nat. Immunol. 15, 957-964 (2014).
224. Saito, M. et al. A signaling pathway mediating downregulation of BCL6 in germinal center B cells is blocked by BCL6 gene alterations in B cell lymphoma. Cancer Cell 12, 280-292 (2007).
225. Ouchi, N., Parker, J. L., Lugus, J. J. & Walsh, K. Adipokines in inflammation and metabolic disease. Nat. Rev. Immunol. 11, 85-97 (2011).
226. Ben-Sasson, S. Z. et al. IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells. J. Exp. Med. 210, 491-502 (2013).
227. Ben-Sasson, S. Z. et al. IL-1 acts directly on CD4 T cells to enhance their antigen-driven expansion and differentiation. Proc. Natl Acad. Sci. USA 106, 7119-7124 (2009).
228. Korn, T., Bettelli, E., Oukka, M. & Kuchroo, V. K. IL-17 and Th17 cells. Annu. Rev. Immunol. 27, 485-517 (2009).
229. + memory T cells. Immunity 38, 131-139 (2013).
230. Tsukamoto, H., Senju, S., Matsumura, K., Swain, S. L. & Nishimura, Y. IL-6-mediated environmental conditioning of defective Th1 differentiation dampens antitumour immune responses in old age. Nat. Commun. 6, 6702 (2015).
231. + T lymphocytes. J. Immunol. 180, 7958-7968 (2008).
232. Lord, G. M. et al. Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394, 897-901 (1998).
233. Saucillo, D. C., Gerriets, V. A., Sheng, J., Rathmell, J. C. & Maciver, N. J. Leptin metabolically licenses T cells for activation to link nutrition and immunity. J. Immunol. 192, 136-144 (2014).
234. Bates, S. H. et al. STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature 421, 856-859 (2003).
235. Priceman, S. J. et al. Regulation of adipose tissue T cell subsets by Stat3 is crucial for diet-induced obesity and insulin resistance. Proc. Natl Acad. Sci. USA 110, 13079-13084 (2013).
236. + T cell subsets and inflammation. J. Clin. Invest. 125, 194-207 (2015).
237. + T cell activation in a mouse model of systemic lupus erythematosus. J. Immunol. 196, 80-90 (2016).
238. Hasegawa, H. et al. Pioglitazone, a peroxisome proliferator-activated receptor gamma activator, ameliorates experimental autoimmune myocarditis by modulating Th1/Th2 balance. J. Mol. Cell Cardiol. 38, 257-265 (2005).
239. Yang, Z., Fujii, H., Mohan, S. V., Goronzy, J. J. & Weyand, C. M. Phosphofructokinase deficiency impairs ATP generation, autophagy, and redox balance in rheumatoid arthritis T cells. J. Exp. Med. 210, 2119-2134 (2013).
240. Yang, Z. et al. Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis. Sci. Transl. Med. 8, 331ra38 (2016).