mTOR, metabolism, and the regulation of T-cell differentiation and function

Immunological Reviews

Volumn 249, Issue 1, 2012, Pages 43-58

  Waickman, Adam T ^a   Powell, Jonathan D ^a  

^a JOHNS HOPKINS UNIVERSITY   (United States)

Author keywords

Anergy; Cell activation; Cell differentiation; T cells; T helper cells

Indexed keywords

HYPOXIA INDUCIBLE FACTOR 1ALPHA; MAMMALIAN TARGET OF RAPAMYCIN; MYC PROTEIN; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA; STEROL REGULATORY ELEMENT BINDING PROTEIN; T LYMPHOCYTE RECEPTOR;

ARTICLE; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CLONAL ANERGY; HUMAN; LYMPHOCYTE DIFFERENTIATION; LYMPHOCYTE FUNCTION; MEMORY T LYMPHOCYTE; METABOLIC REGULATION; METABOLISM; NONHUMAN; PRIORITY JOURNAL; PROTEIN FUNCTION; REGULATORY T LYMPHOCYTE; SIGNAL TRANSDUCTION; T LYMPHOCYTE; T LYMPHOCYTE ACTIVATION; TH1 CELL; TH17 CELL; TH2 CELL; THYMUS; TRANSCRIPTION REGULATION;

ANIMALS; CELL DIFFERENTIATION; ENERGY METABOLISM; HUMANS; LYMPHOCYTE ACTIVATION; PENTOSE PHOSPHATE PATHWAY; RECEPTORS, ANTIGEN, T-CELL; SIGNAL TRANSDUCTION; T-LYMPHOCYTES; TOR SERINE-THREONINE KINASES;

EID: 84865301337     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/j.1600-065X.2012.01152.x     Document Type: Article

References (212)

1. Lafferty KJ, Cunningham AJ. A new analysis of allogeneic interactions. Aust J Exp Biol Med Sci 1975;53:27-42.
2. Bretscher P, Cohn M. A theory of self-nonself discrimination. Science 1970;169:1042-1049.
3. Powell JD, Ragheb JA, Kitagawa-Sakakida S, Schwartz RH. Molecular regulation of interleukin-2 expression by CD28 co-stimulation and anergy. Immunol Rev 1998;165:287-300.
4. Jenkins MK, Taylor PS, Norton SD, Urdahl KB. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J Immunol 1991;147:2461-2466.
5. Colombetti S, Basso V, Mueller DL, Mondino A. Prolonged TCR/CD28 engagement drives IL-2-independent T cell clonal expansion through signaling mediated by the mammalian target of rapamycin. J Immunol 2006;176:2730-2738.
6. O'Garra A. Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 1998;8:275-283.
7. Soroosh P, Doherty TA. Th9 and allergic disease. Immunology 2009;127:450-458.
8. Harrington LE, Mangan PR, Weaver CT. Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Curr Opin Immunol 2006;18:349-356.
9. Rudensky AY. Regulatory T cells and Foxp3. Immunol Rev 2011;241:260-268.
10. Powell JD, Delgoffe GM. The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity 2010;33:301-311.
11. Delgoffe GM, Powell JD. mTOR: taking cues from the immune microenvironment. Immunology 2009;127:459-465.
12. -Laplante M, Sabatini DM. mTOR signaling at a glance. J Cell Sci 2009;122:3589-3594.
13. -Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012;149:274-293.
14. Powell JD, Lerner CG, Schwartz RH. Inhibition of cell cycle progression by rapamycin induces T cell clonal anergy even in the presence of costimulation. J Immunol 1999;162:2775-2784.
15. Delgoffe GM, et al. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 2009;30:832-844.
16. Araki K, et al. mTOR regulates memory CD8 T-cell differentiation. Nature 2009;460:108-112.
17. He S, et al. Characterization of the metabolic phenotype of rapamycin-treated CD8 T cells with augmented ability to generate long-lasting memory cells. PLoS ONE 2011;6:e20107.
18. Rao RR, Li Q, Odunsi K, Shrikant PA. The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity 2010;32:67-78.
19. Zhang S, et al. Constitutive reductions in mTOR alter cell size, immune cell development, and antibody production. Blood 2011;117:1228-1238.
20. Lazorchak AS, et al. Sin1-mTORC2 suppresses rag and il7r gene expression through Akt2 in B cells. Mol Cell 2010;39:433-443.
21. Sathaliyawala T, et al. Mammalian target of rapamycin controls dendritic cell development downstream of Flt3 ligand signaling. Immunity 2010;33:597-606.
22. Turnquist HR, Raimondi G, Zahorchak AF, Fischer RT, Wang Z, Thomson AW. Rapamycin-conditioned dendritic cells are poor stimulators of allogeneic CD4+ T cells, but enrich for antigen-specific Foxp3+ T regulatory cells and promote organ transplant tolerance. J Immunol 2007;178:7018-7031.
23. Weichhart T, et al. The TSC-mTOR signaling pathway regulates the innate inflammatory response. Immunity 2008;29:565-577.
24. Fox CJ, Hammerman PS, Thompson CB. Fuel feeds function: energy metabolism and the T-cell response. Nat Rev Immunol 2005;5:844-852.
25. Bauer DE, et al. Cytokine stimulation of aerobic glycolysis in hematopoietic cells exceeds proliferative demand. FASEB J 2004;18:1303-1305.
26. Frauwirth KA, Thompson CB. Regulation of T lymphocyte metabolism. J Immunol 2004;172:4661-4665.
27. Frauwirth KA, et al. The CD28 signaling pathway regulates glucose metabolism. Immunity 2002;16:769-777.
28. Carr EL, et al. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation. J Immunol 2010;185:1037-1044.
29. Zheng Y, Delgoffe GM, Meyer CF, Chan W, Powell JD. Anergic T cells are metabolically anergic. J Immunol 2009;183:6095-6101.
30. Pearce EL, et al. Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 2009;460:103-107.
31. van der Windt GJ, et al. Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 2012;36:68-78.
32. Yamagata K, et al. rheb, a growth factor- and synaptic activity-regulated gene, encodes a novel Ras-related protein. J Biol Chem 1994;269:16333-16339.
33. Zhang Y, Gao X, Saucedo LJ, Ru B, Edgar BA, Pan D. Rheb is a direct target of the tuberous sclerosis tumour suppressor proteins. Nat Cell Biol 2003;5:578-581.
34. Inoki K, Li Y, Zhu T, Wu J, Guan KL. TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling. Nat Cell Biol 2002;4:648-657.
35. Vander Haar E, Lee SI, Bandhakavi S, Griffin TJ, Kim DH. Insulin signalling to mTOR mediated by the Akt/PKB substrate PRAS40. Nat Cell Biol 2007;9:316-323.
36. Wang L, Harris TE, Roth RA, Lawrence JC Jr. PRAS40 regulates mTORC1 kinase activity by functioning as a direct inhibitor of substrate binding. J Biol Chem 2007;282:20036-20044.
37. Beugnet A, Tee AR, Taylor PM, Proud CG. Regulation of targets of mTOR (mammalian target of rapamycin) signalling by intracellular amino acid availability. Biochem J 2003;372:555-566.
38. Jefferies HB, Reinhard C, Kozma SC, Thomas G. Rapamycin selectively represses translation of the 'polypyrimidine tract' mRNA family. Proc Natl Acad Sci USA 1994;91:4441-4445.
39. Hsieh AC, et al. The translational landscape of mTOR signalling steers cancer initiation and metastasis. Nature 2012;485:55-61.
40. Zinzalla V, Stracka D, Oppliger W, Hall MN. Activation of mTORC2 by association with the ribosome. Cell 2011;144:757-768.
41. Chen CH, et al. ER stress inhibits mTORC2 and Akt signaling through GSK-3beta-mediated phosphorylation of rictor. Sci Signal 2011;4:ra10.
42. Garcia-Martinez JM, Alessi DR. mTOR complex 2 (mTORC2) controls hydrophobic motif phosphorylation and activation of serum- and glucocorticoid-induced protein kinase 1 (SGK1). Biochem J 2008;416:375-385.
43. Guertin DA, et al. Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 2006;11:859-871.
44. Delgoffe GM, et al. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat Immunol 2011;12:295-303.
45. Lee K, et al. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 2010;32:743-753.
46. Exley M, Varticovski L, Peter M, Sancho J, Terhorst C. Association of phosphatidylinositol 3-kinase with a specific sequence of the T cell receptor zeta chain is dependent on T cell activation. J Biol Chem 1994;269:15140-15146.
47. Harada Y, et al. Critical requirement for the membrane-proximal cytosolic tyrosine residue for CD28-mediated costimulation in vivo. J Immunol 2001;166:3797-3803.
48. Kane LP, Andres PG, Howland KC, Abbas AK, Weiss A. Akt provides the CD28 costimulatory signal for up-regulation of IL-2 and IFN-gamma but not TH2 cytokines. Nat Immunol 2001;2:37-44.
49. Fos C, et al. ICOS ligation recruits the p50alpha PI3K regulatory subunit to the immunological synapse. J Immunol 2008;181:1969-1977.
50. Xiao X, et al. New insights on OX40 in the control of t cell immunity and immune tolerance in vivo. J Immunol 2012;188:892-901.
51. So T, Choi H, Croft M. OX40 complexes with phosphoinositide 3-kinase and protein kinase B (PKB) to augment TCR-dependent PKB signaling. J Immunol 2011;186:3547-3555.
52. Ruby CE, Redmond WL, Haley D, Weinberg AD. Anti-OX40 stimulation in vivo enhances CD8+ memory T cell survival and significantly increases recall responses. Eur J Immunol 2007;37:157-166.
53. Parry RV, et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol Cell Biol 2005;25:9543-9553.
54. Chuang E, et al. The CD28 and CTLA-4 receptors associate with the serine/threonine phosphatase PP2A. Immunity 2000;13:313-322.
55. Francisco LM, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 2009;206:3015-3029.
56. Abraham RT, Wiederrecht GJ. Immunopharmacology of rapamycin. Annu Rev Immunol 1996;14:483-510.
57. Stephenson LM, Park DS, Mora AL, Goenka S, Boothby M. Sequence motifs in IL-4R alpha mediating cell-cycle progression of primary lymphocytes. J Immunol 2005;175:5178-5185.
58. Barata JT, Silva A, Brandao JG, Nadler LM, Cardoso AA, Boussiotis VA. Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells. J Exp Med 2004;200:659-669.
59. Curnock AP, Ward SG. Development and characterisation of tetracycline-regulated phosphoinositide 3-kinase mutants: assessing the role of multiple phosphoinositide 3-kinases in chemokine signaling. J Immunol Methods 2003;273:29-41.
60. Sasaki T, et al. Function of PI3Kgamma in thymocyte development, T cell activation, and neutrophil migration. Science 2000;287:1040-1046.
61. Liu G, et al. The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR. Nat Immunol 2009;10:769-777.
62. Liu G, Yang K, Burns S, Shrestha S, Chi H. The S1P(1)-mTOR axis directs the reciprocal differentiation of T(H)1 and T(reg) cells. Nat Immunol 2010;11:1047-1056.
63. Uddin S, Yenush L, Sun XJ, Sweet ME, White MF, Platanias LC. Interferon-alpha engages the insulin receptor substrate-1 to associate with the phosphatidylinositol 3′-kinase. J Biol Chem 1995;270:15938-15941.
64. Platanias LC, Uddin S, Yetter A, Sun XJ, White MF. The type I interferon receptor mediates tyrosine phosphorylation of insulin receptor substrate 2. J Biol Chem 1996;271:278-282.
65. Navarro A, Anand-Apte B, Tanabe Y, Feldman G, Larner AC. A PI-3 kinase-dependent, Stat1-independent signaling pathway regulates interferon-stimulated monocyte adhesion. J Leukoc Biol 2003;73:540-545.
66. Myers MG Jr. Leptin receptor signaling and the regulation of mammalian physiology. Rec Prog Hormone Res 2004;59:287-304.
67. Kellerer M, Koch M, Metzinger E, Mushack J, Capp E, Haring HU. Leptin activates PI-3 kinase in C2C12 myotubes via janus kinase-2 (JAK-2) and insulin receptor substrate-2 (IRS-2) dependent pathways. Diabetologia 1997;40:1358-1362.
68. Galgani M, et al. Leptin modulates the survival of autoreactive CD4+ T cells through the nutrient/energy-sensing mammalian target of rapamycin signaling pathway. J Immunol 2010;185:7474-7479.
69. Sengupta S, Peterson TR, Sabatini DM. Regulation of the mTOR complex 1 pathway by nutrients, growth factors, and stress. Mol Cell 2010;40:310-322.
70. Gwinn DM, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol Cell 2008;30:214-226.
71. Brugarolas J, et al. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes Dev 2004;18:2893-2904.
72. DeYoung MP, Horak P, Sofer A, Sgroi D, Ellisen LW. Hypoxia regulates TSC1/2-mTOR signaling and tumor suppression through REDD1-mediated 14-3-3 shuttling. Genes Dev 2008;22:239-251.
73. Jones RG, et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell 2005;18:283-293.
74. Feng Z, et al. The regulation of AMPK beta1, TSC2, and PTEN expression by p53: stress, cell and tissue specificity, and the role of these gene products in modulating the IGF-1-AKT-mTOR pathways. Cancer Res 2007;67:3043-3053.
75. Ellisen LW, et al. REDD1, a developmentally regulated transcriptional target of p63 and p53, links p63 to regulation of reactive oxygen species. Mol Cell 2002;10:995-1005.
76. Warburg O. On the origin of cancer cells. Science 1956;123:309-314.
77. Jones RG, Thompson CB. Tumor suppressors and cell metabolism: a recipe for cancer growth. Genes Dev 2009;23:537-548.
78. Sun Q, et al. Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor growth. Proc Natl Acad Sci USA 2011;108:4129-4134.
79. Duvel K, et al. Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell 2010;39:171-183.
80. Wang R, et al. The transcription factor Myc controls metabolic reprogramming upon T lymphocyte activation. Immunity 2011;35:871-882.
81. 2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev 1998;12:149-162.
82. Tozzi MG, Camici M, Mascia L, Sgarrella F, Ipata PL. Pentose phosphates in nucleoside interconversion and catabolism. FEBS J 2006;273:1089-1101.
83. Christie GR, Hajduch E, Hundal HS, Proud CG, Taylor PM. Intracellular sensing of amino acids in Xenopus laevis oocytes stimulates p70 S6 kinase in a target of rapamycin-dependent manner. J Biol Chem 2002;277:9952-9957.
84. Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol 2008;10:935-945.
85. Sancak Y, et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science 2008;320:1496-1501.
86. Cohen A, Hall MN. An amino acid shuffle activates mTORC1. Cell 2009;136:399-400.
87. Nicklin P, et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 2009;136:521-534.
88. Sipula IJ, Brown NF, Perdomo G. Rapamycin-mediated inhibition of mammalian target of rapamycin in skeletal muscle cells reduces glucose utilization and increases fatty acid oxidation. Metab, Clin Exp 2006;55:1637-1644.
89. Brown NF, Stefanovic-Racic M, Sipula IJ, Perdomo G. The mammalian target of rapamycin regulates lipid metabolism in primary cultures of rat hepatocytes. Metab, Clin Exp 2007;56:1500-1507.
90. Michalek RD, et al. Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets. J Immunol 2011;186:3299-3303.
91. Schieke SM, et al. The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem 2006;281:27643-27652.
92. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 2007;450:736-740.
93. Rubinsztein DC. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 2006;443:780-786.
94. Mizushima N. Autophagy: process and function. Genes Dev 2007;21:2861-2873.
95. Kabeya Y, Mizushima N, Yamamoto A, Oshitani-Okamoto S, Ohsumi Y, Yoshimori T. LC3, GABARAP and GATE16 localize to autophagosomal membrane depending on form-II formation. J Cell Sci 2004;117:2805-2812.
96. Pattingre S, Espert L, Biard-Piechaczyk M, Codogno P. Regulation of macroautophagy by mTOR and Beclin 1 complexes. Biochimie 2008;90:313-323.
97. Blommaart EF, Luiken JJ, Blommaart PJ, van Woerkom GM, Meijer AJ. Phosphorylation of ribosomal protein S6 is inhibitory for autophagy in isolated rat hepatocytes. J Biol Chem 1995;270:2320-2326.
98. Ng S, Wu YT, Chen B, Zhou J, Shen HM. Impaired autophagy due to constitutive mTOR activation sensitizes TSC2-null cells to cell death under stress. Autophagy 2011;7:1173-1186.
99. Nakatogawa H, Suzuki K, Kamada Y, Ohsumi Y. Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 2009;10:458-467.
100. Jung CH, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 2009;20:1992-2003.
101. Ganley IG, Lam du H, Wang J, Ding X, Chen S, Jiang X. ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 2009;284:12297-12305.
102. Chan EY, Kir S, Tooze SA. siRNA screening of the kinome identifies ULK1 as a multidomain modulator of autophagy. J Biol Chem 2007;282:25464-25474.
103. Semenza GL. Hypoxia-inducible factor 1 (HIF-1) pathway. Sci STKE 2007;2007:cm8.
104. Maxwell PH, et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999;399:271-275.
105. Bruick RK, McKnight SL. A conserved family of prolyl-4-hydroxylases that modify HIF. Science 2001;294:1337-1340.
106. Seagroves TN, et al. Transcription factor HIF-1 is a necessary mediator of the pasteur effect in mammalian cells. Mol Cell Biol 2001;21:3436-3444.
107. Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab 2006;3:177-185.
108. Hudson CC, et al. Regulation of hypoxia-inducible factor 1alpha expression and function by the mammalian target of rapamycin. Mol Cell Biol 2002;22:7004-7014.
109. Majumder PK, et al. mTOR inhibition reverses Akt-dependent prostate intraepithelial neoplasia through regulation of apoptotic and HIF-1-dependent pathways. Nat Med 2004;10:594-601.
110. Nakamura H, et al. TCR engagement increases hypoxia-inducible factor-1 alpha protein synthesis via rapamycin-sensitive pathway under hypoxic conditions in human peripheral T cells. J Immunol 2005;174:7592-7599.
111. Treins C, Giorgetti-Peraldi S, Murdaca J, Monthouel-Kartmann MN, Van Obberghen E. Regulation of hypoxia-inducible factor (HIF)-1 activity and expression of HIF hydroxylases in response to insulin-like growth factor I. Mol Endocrinol 2005;19:1304-1317.
112. Zhou J, et al. Regulation of hypoxia-inducible factor 1 by glucose availability under hypoxic conditions. Kobe J Med Sci 2007;53:283-296.
113. Sofer A, Lei K, Johannessen CM, Ellisen LW. Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol Cell Biol 2005;25:5834-5845.
114. Dang CV, Semenza GL. Oncogenic alterations of metabolism. Trends Biochem Sci 1999;24:68-72.
115. Gordan JD, Thompson CB, Simon MC. HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 2007;12:108-113.
116. Nilsson JA, Cleveland JL. Myc pathways provoking cell suicide and cancer. Oncogene 2003;22:9007-9021.
117. Sears RC. The life cycle of C-myc: from synthesis to degradation. Cell Cycle 2004;3:1133-1137.
118. West MJ, Stoneley M, Willis AE. Translational induction of the c-myc oncogene via activation of the FRAP/TOR signalling pathway. Oncogene 1998;17:769-780.
119. Murooka TT, Rahbar R, Fish EN. CCL5 promotes proliferation of MCF-7 cells through mTOR-dependent mRNA translation. Biochem Biophys Res Commun 2009;387:381-386.
120. Shi Y, Sharma A, Wu H, Lichtenstein A, Gera J. Cyclin D1 and c-myc internal ribosome entry site (IRES)-dependent translation is regulated by AKT activity and enhanced by rapamycin through a p38 MAPK- and ERK-dependent pathway. J Biol Chem 2005;280:10964-10973.
121. Marderosian M, et al. Tristetraprolin regulates Cyclin D1 and c-Myc mRNA stability in response to rapamycin in an Akt-dependent manner via p38 MAPK signaling. Oncogene 2006;25:6277-6290.
122. Jo OD, Martin J, Bernath A, Masri J, Lichtenstein A, Gera J. Heterogeneous nuclear ribonucleoprotein A1 regulates cyclin D1 and c-myc internal ribosome entry site function through Akt signaling. J Biol Chem 2008;283:23274-23287.
123. Vartanian R, et al. AP-1 regulates cyclin D1 and c-MYC transcription in an AKT-dependent manner in response to mTOR inhibition: role of AIP4/Itch-mediated JUNB degradation. Mol Cancer Res 2011;9:115-130.
124. Schmidt EV, Ravitz MJ, Chen L, Lynch M. Growth controls connect: interactions between c-myc and the tuberous sclerosis complex-mTOR pathway. Cell Cycle 2009;8:1344-1351.
125. Hosoi H, et al. Studies on the mechanism of resistance to rapamycin in human cancer cells. Mol Pharmacol 1998;54:815-824.
126. Lefebvre P, Chinetti G, Fruchart JC, Staels B. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest 2006;116:571-580.
127. Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci USA 1997;94:4312-4317.
128. Kliewer SA, et al. Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma. Proc Natl Acad Sci U A 1997;94:4318-4323.
129. Hostetler HA, Petrescu AD, Kier AB, Schroeder F. Peroxisome proliferator-activated receptor alpha interacts with high affinity and is conformationally responsive to endogenous ligands. J Biol Chem 2005;280:18667-18682.
130. Xu HE, et al. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 1999;3:397-403.
131. Brandt JM, Djouadi F, Kelly DP. Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha. J Biol Chem 1998;273:23786-23792.
132. Rodriguez JC, Gil-Gomez G, Hegardt FG, Haro D. Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids. J Biol Chem 1994;269:18767-18772.
133. Motojima K, Passilly P, Peters JM, Gonzalez FJ, Latruffe N. Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner. J Biol Chem 1998;273:16710-16714.
134. Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. Peroxisome proliferator-activated receptor alpha mediates the adaptive response to fasting. J Clin Invest 1999;103:1489-1498.
135. Delerive P, et al. Peroxisome proliferator-activated receptor activators inhibit thrombin-induced endothelin-1 production in human vascular endothelial cells by inhibiting the activator protein-1 signaling pathway. Circ Res 1999;85:394-402.
136. Delerive P, Gervois P, Fruchart JC, Staels B. Induction of IkappaBalpha expression as a mechanism contributing to the anti-inflammatory activities of peroxisome proliferator-activated receptor-alpha activators. J Biol Chem 2000;275:36703-36707.
137. Delerive P, et al. Peroxisome proliferator-activated receptor alpha negatively regulates the vascular inflammatory gene response by negative cross-talk with transcription factors NF-kappaB and AP-1. J Biol Chem 1999;274:32048-32054.
138. Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM. mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 2010;468:1100-1104.
139. Tontonoz P, Hu E, Spiegelman BM. Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 1994;79:1147-1156.
140. Fajas L, Fruchart JC, Auwerx J. PPARgamma3 mRNA: a distinct PPARgamma mRNA subtype transcribed from an independent promoter. FEBS Lett 1998;438:55-60.
141. Spiegelman BM, Flier JS. Adipogenesis and obesity: rounding out the big picture. Cell 1996;87:377-389.
142. Rosen ED, et al. PPAR gamma is required for the differentiation of adipose tissue in vivo and in vitro. Mol Cell 1999;4:611-617.
143. Forman BM, Tontonoz P, Chen J, Brun RP, Spiegelman BM, Evans RM. 15-Deoxy-delta 12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPAR gamma. Cell 1995;83:803-812.
144. Willson TM, Brown PJ, Sternbach DD, Henke BR. The PPARs: from orphan receptors to drug discovery. J Med Chem 2000;43:527-550.
145. Kim JE, Chen J. regulation of peroxisome proliferator-activated receptor-gamma activity by mammalian target of rapamycin and amino acids in adipogenesis. Diabetes 2004;53:2748-2756.
146. Zhang HH, et al. Insulin stimulates adipogenesis through the Akt-TSC2-mTORC1 pathway. PLoS ONE 2009;4:e6189.
147. Bengoechea-Alonso MT, Ericsson J. SREBP in signal transduction: cholesterol metabolism and beyond. Curr Opin Cell Biol 2007;19:215-222.
148. Porstmann T, et al. SREBP activity is regulated by mTORC1 and contributes to Akt-dependent cell growth. Cell Metab 2008;8:224-236.
149. Bakan I, Laplante M. Connecting mTORC1 signaling to SREBP-1 activation. Curr Opin Lipidol 2012;23:226-234.
150. Yecies JL, et al. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1-dependent and independent pathways. Cell Metab 2011;14:21-32.
151. Amemiya-Kudo M, et al. Promoter analysis of the mouse sterol regulatory element-binding protein-1c gene. J Biol Chem 2000;275:31078-31085.
152. Peterson TR, et al. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 2011;146:408-420.
153. De Boer RJ, Oprea M, Antia R, Murali-Krishna K, Ahmed R, Perelson AS. Recruitment times, proliferation, and apoptosis rates during the CD8(+) T-cell response to lymphocytic choriomeningitis virus. J Virol 2001;75:10663-10669.
154. Morris GP, Allen PM. How the TCR balances sensitivity and specificity for the recognition of self and pathogens. Nat Immunol 2012;13:121-128.
155. Kelly AP, et al. Notch-induced T cell development requires phosphoinositide-dependent kinase 1. EMBO J 2007;26:3441-3450.
156. Tamas P, et al. LKB1 is essential for the proliferation of T-cell progenitors and mature peripheral T cells. Eur J Immunol 2010;40:242-253.
157. Ciofani M, Zuniga-Pflucker JC. Notch promotes survival of pre-T cells at the beta-selection checkpoint by regulating cellular metabolism. Nat Immunol 2005;6:881-888.
158. Lee K, et al. Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia. J Exp Med 2012;209:713-728.
159. Yang K, Neale G, Green DR, He W, Chi H. The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat Immunol 2011;12:888-897.
160. Wu Q, et al. The tuberous sclerosis complex-mammalian target of rapamycin pathway maintains the quiescence and survival of naive T cells. J Immunol 2011;187:1106-1112.
161. O'Brien TF, et al. Regulation of T-cell survival and mitochondrial homeostasis by TSC1. Eur J Immunol 2011;41:3361-3370.
162. Pua HH, Guo J, Komatsu M, He YW. Autophagy is essential for mitochondrial clearance in mature T lymphocytes. J Immunol 2009;182:4046-4055.
163. Li C, et al. Autophagy is induced in CD4+ T cells and important for the growth factor-withdrawal cell death. J Immunol 2006;177:5163-5168.
164. Pua HH, Dzhagalov I, Chuck M, Mizushima N, He YW. A critical role for the autophagy gene Atg5 in T cell survival and proliferation. J Exp Med 2007;204:25-31.
165. Jia W, He YW. Temporal regulation of intracellular organelle homeostasis in T lymphocytes by autophagy. J Immunol 2011;186:5313-5322.
166. Jia W, Pua HH, Li QJ, He YW. Autophagy regulates endoplasmic reticulum homeostasis and calcium mobilization in T lymphocytes. J Immunol 2011;186:1564-1574.
167. Wahl DR, Petersen B, Warner R, Richardson BC, Glick GD, Opipari AW. Characterization of the metabolic phenotype of chronically activated lymphocytes. Lupus 2010;19:1492-1501.
168. Gatza E, et al. Manipulating the bioenergetics of alloreactive T cells causes their selective apoptosis and arrests graft-versus-host disease. Sci Transl Med 2011;3:67ra68.
169. Gergely P Jr, Niland B, Gonchoroff N, Pullmann R Jr, Phillips PE, Perl A. Persistent mitochondrial hyperpolarization, increased reactive oxygen intermediate production, and cytoplasmic alkalinization characterize altered IL-10 signaling in patients with systemic lupus erythematosus. J Immunol 2002;169:1092-1101.
170. Gergely P Jr, et al. Mitochondrial hyperpolarization and ATP depletion in patients with systemic lupus erythematosus. Arthritis Rheum 2002;46:175-190.
171. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 2000;100:655-669.
172. Dunn SE, et al. Peroxisome proliferator-activated receptor (PPAR)alpha expression in T cells mediates gender differences in development of T cell-mediated autoimmunity. J Exp Med 2007;204:321-330.
173. Clark RB, Bishop-Bailey D, Estrada-Hernandez T, Hla T, Puddington L, Padula SJ. The nuclear receptor PPAR gamma and immunoregulation: PPAR gamma mediates inhibition of helper T cell responses. J Immunol 2000;164:1364-1371.
174. Cunard R, Eto Y, Muljadi JT, Glass CK, Kelly CJ, Ricote M. Repression of IFN-gamma expression by peroxisome proliferator-activated receptor gamma. J Immunol 2004;172:7530-7536.
175. Bassaganya-Riera J, et al. Activation of PPAR gamma and delta by conjugated linoleic acid mediates protection from experimental inflammatory bowel disease. Gastroenterology 2004;127:777-791.
176. Beales PE, et al. Troglitazone prevents insulin dependent diabetes in the non-obese diabetic mouse. Eur J Pharmacol 1998;357:221-225.
177. Diab A, et al. Peroxisome proliferator-activated receptor-gamma agonist 15-deoxy-Delta(12, 14)-prostaglandin J(2) ameliorates experimental autoimmune encephalomyelitis. J Immunol 2002;168:2508-2515.
178. Feinstein DL, et al. Peroxisome proliferator-activated receptor-gamma agonists prevent experimental autoimmune encephalomyelitis. Ann Neurol 2002;51:694-702.
179. Mueller C, Weaver V, Vanden Heuvel JP, August A, Cantorna MT. Peroxisome proliferator-activated receptor gamma ligands attenuate immunological symptoms of experimental allergic asthma. Arch Biochem Biophys 2003;418:186-196.
180. Housley WJ, et al. Peroxisome proliferator-activated receptor gamma is required for CD4+ T cell-mediated lymphopenia-associated autoimmunity. J Immunol 2011;187:4161-4169.
181. Guo J, Lu W, Shimoda LA, Semenza GL, Georas SN. Enhanced interferon-gamma gene expression in T cells and reduced ovalbumin-dependent lung eosinophilia in hypoxia-inducible factor-1-alpha-deficient mice. Int Arch Allergy Immunol 2009;149:98-102.
182. Lukashev D, et al. 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 2006;177:4962-4965.
183. Dang EV, et al. Control of T(H)17/T(reg) balance by hypoxia-inducible factor 1. Cell 2011;146:772-784.
184. Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986;136:2348-2357.
185. Zheng W, Flavell RA. The transcription factor GATA-3 is necessary and sufficient for Th2 cytokine gene expression in CD4 T cells. Cell 1997;89:587-596.
186. Shi LZ, et al. HIF1alpha-dependent glycolytic pathway orchestrates a metabolic checkpoint for the differentiation of TH17 and Treg cells. J Exp Med 2011;208:1367-1376.
187. Chung SW, Kang BY, Kim TS. Inhibition of interleukin-4 production in CD4+ T cells by peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligands: involvement of physical association between PPAR-gamma and the nuclear factor of activated T cells transcription factor. Mol Pharmacol 2003;64:1169-1179.
188. Peters A, Lee Y, Kuchroo VK. The many faces of Th17 cells. Curr Opin Immunol 2011;23:702-706.
189. Klotz L, et al. The nuclear receptor PPAR gamma selectively inhibits Th17 differentiation in a T cell-intrinsic fashion and suppresses CNS autoimmunity. J Exp Med 2009;206:2079-2089.
190. Cui G, et al. Liver X receptor (LXR) mediates negative regulation of mouse and human Th17 differentiation. J Clin Invest 2011;121:658-670.
191. Josefowicz SZ, Rudensky A. Control of regulatory T cell lineage commitment and maintenance. Immunity 2009;30:616-625.
192. Collison LW, et al. IL-35-mediated induction of a potent regulatory T cell population. Nat Immunol 2010;11:1093-1101.
193. Lei J, Hasegawa H, Matsumoto T, Yasukawa M. Peroxisome proliferator-activated receptor alpha and gamma agonists together with TGF-beta convert human CD4+CD25- T cells into functional Foxp3+ regulatory T cells. J Immunol 2010;185:7186-7198.
194. Wohlfert EA, Nichols FC, Nevius E, Clark RB. Peroxisome proliferator-activated receptor gamma (PPARgamma) and immunoregulation: enhancement of regulatory T cells through PPARgamma-dependent and -independent mechanisms. J Immunol 2007;178:4129-4135.
195. Hontecillas R, Bassaganya-Riera J. Peroxisome proliferator-activated receptor gamma is required for regulatory CD4+ T cell-mediated protection against colitis. J Immunol 2007;178:2940-2949.
196. Kang J, Huddleston SJ, Fraser JM, Khoruts A. De novo induction of antigen-specific CD4+CD25+Foxp3+ regulatory T cells in vivo following systemic antigen administration accompanied by blockade of mTOR. J Leukoc Biol 2008;83:1230-1239.
197. Haxhinasto S, Mathis D, Benoist C. The AKT-mTOR axis regulates de novo differentiation of CD4+Foxp3+ cells. J Exp Med 2008;205:565-574.
198. Zeiser R, et al. Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood 2008;111:453-462.
199. Sauer S, et al. T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR. Proc Natl Acad Sci USA 2008;105:7797-7802.
200. Procaccini C, et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 2010;33:929-941.
201. Gabrysova L, Christensen JR, Wu X, Kissenpfennig A, Malissen B, O'Garra A. Integrated T-cell receptor and costimulatory signals determine TGF-beta-dependent differentiation and maintenance of Foxp3+ regulatory T cells. Eur J Immunol 2011;41:1242-1248.
202. Katzman SD, et al. Duration of antigen receptor signaling determines T-cell tolerance or activation. Proc Natl Acad Sci USA 2010;107:18085-18090.
203. Gottschalk RA, Corse E, Allison JP. TCR ligand density and affinity determine peripheral induction of Foxp3 in vivo. J Exp Med 2010;207:1701-1711.
204. Chappert P, Schwartz RH. Induction of T cell anergy: integration of environmental cues and infectious tolerance. Curr Opin Immunol 2010;22:552-559.
205. Schwartz RH. T cell anergy. Annu Rev Immunol 2003;21:305-334.
206. Zheng Y, et al. A role for mammalian target of rapamycin in regulating T cell activation versus anergy. J Immunol 2007;178:2163-2170.
207. Vanasek TL, Khoruts A, Zell T, Mueller DL. Antagonistic roles for CTLA-4 and the mammalian target of rapamycin in the regulation of clonal anergy: enhanced cell cycle progression promotes recall antigen responsiveness. J Immunol 2001;167:5636-5644.
208. Li Q, et al. A central role for mTOR kinase in homeostatic proliferation induced CD8+ T cell memory and tumor immunity. Immunity 2011;34:541-553.
209. Cheung KP, Yang E, Goldrath AW. Memory-like CD8+ T cells generated during homeostatic proliferation defer to antigen-experienced memory cells. J Immunol 2009;183:3364-3372.
210. Cho BK, Rao VP, Ge Q, Eisen HN, Chen J. Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells. J Exp Med 2000;192:549-556.
211. Dummer W, et al. T cell homeostatic proliferation elicits effective antitumor autoimmunity. J Clin Invest 2002;110:185-192.
212. Ma J, Urba WJ, Si L, Wang Y, Fox BA, Hu HM. Anti-tumor T cell response and protective immunity in mice that received sublethal irradiation and immune reconstitution. Eur J Immunol 2003;33:2123-2132.