The discovery of interleukin-2 (IL-2) changed the molecular understanding of how the immune system is controlled. IL-2 is a pleiotropic cytokine, and dissecting the signaling pathways that allow IL-2 to control the differentiation and homeostasis of both pro- and anti-inflammatory T cells is fundamental to determining the molecular details of immune regulation. The IL-2 receptor couples to JAK tyrosine kinases and activates the STAT5 transcription factors. However, IL-2 does much more than control transcriptional programs; it is a key regulator of T cell metabolic programs. The development of global phosphoproteomic approaches has expanded the understanding of IL-2 signaling further, revealing the diversity of phosphoproteins that may be influenced by IL-2 in T cells. However, it is increasingly clear that within each T cell subset, IL-2 will signal within a framework of other signal transduction networks that together will shape the transcriptional and metabolic programs that determine T cell fate.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Morgan DA, Ruscetti FW, Gallo R. 1.  1976. Selective in vitro growth of T lymphocytes from normal human bone marrows. Science 193:42571007–8 [Google Scholar]
  2. Gillis S, Smith KA. 2.  1977. Long term culture of tumour-specific cytotoxic T cells. Nature 268:5616154–56 [Google Scholar]
  3. Gillis S, Baker PE, Ruscetti FW, Smith KA. 3.  1978. Long-term culture of human antigen-specific cytotoxic T-cell lines. J. Exp. Med. 148:41093–98 [Google Scholar]
  4. Smith KA. 4.  1988. Interleukin-2: inception, impact, and implications. Science 240:48561169–76 [Google Scholar]
  5. Cantrell DA, Smith KA. 5.  1983. Transient expression of interleukin 2 receptors: consequences for T cell growth. J. Exp. Med. 158:61895–911 [Google Scholar]
  6. Meuer SC, Hussey RE, Cantrell DA, Hodgdon JC, Schlossman SF. 6.  et al. 1984. Triggering of the T3-Ti antigen-receptor complex results in clonal T-cell proliferation through an interleukin 2-dependent autocrine pathway. PNAS 81:51509–13 [Google Scholar]
  7. Robb RJ, Smith KA. 7.  1981. Heterogeneity of human T-cell growth factor(s) due to variable glycosylation. Mol. Immunol. 18:121087–94 [Google Scholar]
  8. Robb RJ, Kutny RM, Chowdhry V. 8.  1983. Purification and partial sequence analysis of human T-cell growth factor. PNAS 80:195990–94 [Google Scholar]
  9. Smith KA, Cantrell DA. 9.  1985. Interleukin 2 regulates its own receptors. PNAS 82:3864–68 [Google Scholar]
  10. Leonard WJ, Depper JM, Crabtree GR, Rudikoff S, Pumphrey J. 10.  et al. 1984. Molecular cloning and expression of cDNAs for the human interleukin-2 receptor. Nature 311:5987626–31 [Google Scholar]
  11. Nikaido T, Shimizu A, Ishida N, Sabe H, Teshigawara K. 11.  et al. 1984. Molecular cloning of cDNA encoding human interleukin-2 receptor. Nature 311:5987631–35 [Google Scholar]
  12. Sharon M, Klausner R, Cullen B, Chizzonite R, Leonard W. 12.  1986. Novel interleukin-2 receptor subunit detected by cross-linking under high-affinity conditions. Science 234:4778859–63 [Google Scholar]
  13. Sugamura K, Takeshita T, Asao H, Kumaki S, Ohbo K. 13.  et al. 1992. The IL-2/IL-2 receptor system: involvement of a novel receptor subunit, gamma chain, in growth signal transduction. Tohoku J. Exp. Med. 168:2231–37 [Google Scholar]
  14. Takeshita T, Asao H, Ohtani K, Ishii N, Kumaki S. 14.  et al. 1992. Cloning of the gamma chain of the human IL-2 receptor. Science 257:5068379–82 [Google Scholar]
  15. Liao W, Lin J-X, Leonard WJ. 15.  2013. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38:113–25 [Google Scholar]
  16. Feinerman O, Jentsch G, Tkach KE, Coward JW, Hathorn MM. 16.  et al. 2010. Single-cell quantification of IL-2 response by effector and regulatory T cells reveals critical plasticity in immune response. Mol. Syst. Biol. 6:437 [Google Scholar]
  17. Hukelmann JL, Anderson KE, Sinclair LV, Grzes KM, Murillo AB. 17.  et al. 2016. The cytotoxic T cell proteome and its shaping by the kinase mTOR. Nat. Immunol. 17:1104–12 [Google Scholar]
  18. Rochman Y, Spolski R, Leonard WJ. 18.  2009. New insights into the regulation of T cells by γc family cytokines. Nat. Rev. Immunol. 9:7480–90 [Google Scholar]
  19. Noguchi M, Yi H, Rosenblatt HM, Filipovich AH, Adelstein S. 19.  et al. 1993. Interleukin-2 receptor gamma chain mutation results in X-linked severe combined immunodeficiency in humans. Cell 73:1147–57 [Google Scholar]
  20. Macian F. 20.  2005. NFAT proteins: key regulators of T-cell development and function. Nat. Rev. Immunol. 5:6472–84 [Google Scholar]
  21. Schorle H, Holtschke T, Hünig T, Schimpl A, Horak I. 21.  1991. Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352:6336621–24 [Google Scholar]
  22. Sadlack B, Merz H, Schorle H, Schimpl A, Feller AC, Horak I. 22.  1993. Ulcerative colitis-like disease in mice with a disrupted interleukin-2 gene. Cell 75:2253–61 [Google Scholar]
  23. Willerford DM, Chen J, Ferry JA, Davidson L, Ma A. 23.  1995. Interleukin-2 receptor α chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3:4521–30 [Google Scholar]
  24. Sharfe N, Dadi HK, Shahar M, Roifman CM. 24.  1997. Human immune disorder arising from mutation of the alpha chain of the interleukin-2 receptor. PNAS 94:73168–71 [Google Scholar]
  25. Gregersen PK, Olsson LM. 25.  2009. Recent advances in the genetics of autoimmune disease. Annu. Rev. Immunol. 27:363–91 [Google Scholar]
  26. Todd JA. 26.  2010. Etiology of type 1 diabetes. Immunity 32:4457–67 [Google Scholar]
  27. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. 27.  2005. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6:111142–51 [Google Scholar]
  28. Cheng G, Yu A, Malek TR. 28.  2011. T-cell tolerance and the multi-functional role of IL-2R signaling in T-regulatory cells. Immunol. Rev. 241:163–76 [Google Scholar]
  29. Rudensky AY. 29.  2011. Regulatory T cells and Foxp3. Immunol. Rev. 241:1260–68 [Google Scholar]
  30. Malek TR. 30.  2008. The biology of interleukin-2. Annu. Rev. Immunol. 26:453–79 [Google Scholar]
  31. Cote-Sierra J, Foucras G, Guo L, Chiodetti L, Young HA. 31.  et al. 2004. Interleukin 2 plays a central role in Th2 differentiation. PNAS 101:113880–85 [Google Scholar]
  32. Laurence A, Tato CM, Davidson TS, Kanno Y, Chen Z. 32.  et al. 2007. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity 26:3371–81 [Google Scholar]
  33. Kalia V, Sarkar S, Subramaniam S, Haining WN, Smith KA, Ahmed R. 33.  2010. Prolonged interleukin-2Rα expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo. Immunity 32:191–103 [Google Scholar]
  34. Pipkin ME, Sacks JA, Cruz-Guilloty F, Lichtenheld MG, Bevan MJ, Rao A. 34.  2010. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells. Immunity 32:179–90 [Google Scholar]
  35. Liao W, Lin J-X, Leonard WJ. 35.  2011. IL-2 family cytokines: new insights into the complex roles of IL-2 as a broad regulator of T helper cell differentiation. Curr. Opin. Immunol. 23:5598–604 [Google Scholar]
  36. Liao W, Lin J-X, Wang L, Li P, Leonard WJ. 36.  2011. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages. Nat. Immunol. 12:6551–59 [Google Scholar]
  37. Ballesteros-Tato A, León B, Graf BA, Moquin A, Adams PS. 37.  et al. 2012. Interleukin-2 inhibits germinal center formation by limiting T follicular helper cell differentiation. Immunity 36:5847–56 [Google Scholar]
  38. Boyman O, Sprent J. 38.  2012. The role of interleukin-2 during homeostasis and activation of the immune system. Nat. Rev. Immunol. 12:3180–90 [Google Scholar]
  39. O'Shea JJ, Paul WE. 39.  2010. Mechanisms underlying lineage commitment and plasticity of helper CD4+ T cells. Science 327:59691098–102 [Google Scholar]
  40. Johnston RJ, Poholek AC, DiToro D, Yusuf I, Eto D. 40.  et al. 2009. Bcl6 and Blimp-1 are reciprocal and antagonistic regulators of T follicular helper cell differentiation. Science 325:59431006–10 [Google Scholar]
  41. Liao W, Schones DE, Oh J, Cui Y, Cui K. 41.  et al. 2008. Priming for T helper type 2 differentiation by interleukin 2-mediated induction of interleukin 4 receptor α-chain expression. Nat. Immunol. 9:111288–96 [Google Scholar]
  42. Yang X-P, Ghoreschi K, Steward-Tharp SM, Rodriguez-Canales J, Zhu J. 42.  et al. 2011. Opposing regulation of the locus encoding IL-17 through direct, reciprocal actions of STAT3 and STAT5. Nat. Immunol. 12:3247–54 [Google Scholar]
  43. Ray JP, Staron MM, Shyer JA, Ho P-C, Marshall HD. 43.  et al. 2015. The interleukin-2-mTORC1 kinase axis defines the signaling, differentiation, and metabolism of T helper 1 and follicular B helper T cells. Immunity 43:4690–702 [Google Scholar]
  44. Hinrichs CS, Spolski R, Paulos CM, Gattinoni L, Kerstann KW. 44.  et al. 2008. IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood 111:115326–33 [Google Scholar]
  45. Gong D, Malek TR. 45.  2007. Cytokine-dependent Blimp-1 expression in activated T cells inhibits IL-2 production. J. Immunol. 178:1242–52 [Google Scholar]
  46. Oestreich KJ, Huang AC, Weinmann AS. 46.  2011. The lineage-defining factors T-bet and Bcl-6 collaborate to regulate Th1 gene expression patterns. J. Exp. Med. 208:51001–13 [Google Scholar]
  47. Oestreich KJ, Mohn SE, Weinmann AS. 47.  2012. Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile. Nat. Immunol. 13:4405–11 [Google Scholar]
  48. Xue H-H, Kovanen PE, Pise-Masison CA, Berg M, Radovich MF. 48.  et al. 2002. IL-2 negatively regulates IL-7 receptor α chain expression in activated T lymphocytes. PNAS 99:2113759–64 [Google Scholar]
  49. Reem GH, Yeh NH. 49.  1984. Interleukin 2 regulates expression of its receptor and synthesis of gamma interferon by human T lymphocytes. Science 225:4660429–30 [Google Scholar]
  50. Kasahara T, Hooks JJ, Dougherty SF, Oppenheim JJ. 50.  1983. Interleukin 2-mediated immune interferon (IFN-gamma) production by human T cells and T cell subsets. J. Immunol. 130:41784–89 [Google Scholar]
  51. Lin J-X, Li P, Liu D, Jin H-T, He J. 51.  et al. 2012. Critical role of STAT5 transcription factor tetramerization for cytokine responses and normal immune function. Immunity 36:4586–99 [Google Scholar]
  52. Janas ML, Groves P, Kienzle N, Kelso A. 52.  2005. IL-2 regulates perforin and granzyme gene expression in CD8+ T cells independently of its effects on survival and proliferation. J. Immunol. 175:128003–10 [Google Scholar]
  53. Cornish GH, Sinclair LV, Cantrell DA. 53.  2006. Differential regulation of T-cell growth by IL-2 and IL-15. Blood 108:2600–8 [Google Scholar]
  54. Sinclair LV, Rolf J, Emslie E, Shi Y-B, Taylor PM, Cantrell DA. 54.  2013. Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation. Nat. Immunol. 14:5500–8 [Google Scholar]
  55. Ross SH, Rollings C, Anderson KE, Hawkins PT, Stephens LR, Cantrell DA. 55.  2016. Phosphoproteomic analyses of interleukin 2 signaling reveal integrated JAK kinase-dependent and -independent networks in CD8+ T cells. Immunity 45:3685–700 [Google Scholar]
  56. Manjunath N, Shankar P, Wan J, Weninger W, Crowley MA. 56.  et al. 2001. Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes. J. Clin. Investig. 108:6871–78 [Google Scholar]
  57. Feau S, Arens R, Togher S, Schoenberger SP. 57.  2011. Autocrine IL-2 is required for secondary population expansion of CD8+ memory T cells. Nat. Immunol. 12:9908–13 [Google Scholar]
  58. Sa Q, Woodward J, Suzuki Y. 58.  2013. IL-2 produced by CD8+ immune T cells can augment their IFN-γ production independently from their proliferation in the secondary response to an intracellular pathogen. J. Immunol. 190:52199–207 [Google Scholar]
  59. Graves JD, Downward J, Izquierdo Pastor M, Rayter S, Warne PH, Cantrell DA. 59.  1992. The growth factor IL-2 activates p21ras proteins in normal human T lymphocytes. J. Immunol. 148:82417–22 [Google Scholar]
  60. Wellbrock C, Karasarides M, Marais R. 60.  2004. The RAF proteins take centre stage. Nat. Rev. Mol. Cell Biol. 5:11875–85 [Google Scholar]
  61. Kuo CJ, Chung J, Fiorentino DF, Flanagan WM, Blenis J, Crabtree GR. 61.  1992. Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature 358:638170–73 [Google Scholar]
  62. Brennan P, Babbage JW, Burgering BM, Groner B, Reif K, Cantrell DA. 62.  1997. Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. Immunity 7:5679–89 [Google Scholar]
  63. Reif K, Burgering BM, Cantrell DA. 63.  1997. Phosphatidylinositol 3-kinase links the interleukin-2 receptor to protein kinase B and p70 S6 kinase. J. Biol. Chem. 272:2214426–33 [Google Scholar]
  64. Finlay DK, Rosenzweig E, Sinclair LV, Feijoo-Carnero C, Hukelmann JL. 64.  et al. 2012. PDK1 regulation of mTOR and hypoxia-inducible factor 1 integrate metabolism and migration of CD8+ T cells. J. Exp. Med. 209:132441–53 [Google Scholar]
  65. Delespine-Carmagnat M, Bouvier G, Allée G, Fagard R, Bertoglio J. 65.  1999. Biochemical analysis of interleukin-2 receptor β chain phosphorylation by p56lck. FEBS Lett 447:2–3241–46 [Google Scholar]
  66. Hatakeyama M, Kono T, Kobayashi N, Kawahara A, Levin SD. 66.  et al. 1991. Interaction of the IL-2 receptor with the src-family kinase p56lck: identification of novel intermolecular association. Science 252:50121523–28 [Google Scholar]
  67. Johnston JA, Kawamura M, Kirken RA, Chen YQ, Blake TB. 67.  et al. 1994. Phosphorylation and activation of the Jak-3 Janus kinase in response to interleukin-2. Nature 370:6485151–53 [Google Scholar]
  68. Russell SM, Johnston JA, Noguchi M, Kawamura M, Bacon CM. 68.  et al. 1994. Interaction of IL-2R beta and gamma c chains with Jak1 and Jak3: implications for XSCID and XCID. Science 266:51871042–45 [Google Scholar]
  69. Witthuhn BA, Silvennoinen O, Miura O, Lai KS, Cwik C. 69.  et al. 1994. Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature 370:6485153–57 [Google Scholar]
  70. Suzuki K. 70.  2000. Janus kinase 3 (Jak3) is essential for common cytokine receptor γ chain (γc)-dependent signaling: comparative analysis of γc, Jak3, and γc and Jak3 double-deficient mice. Int. Immunol. 12:2123–32 [Google Scholar]
  71. Miyazaki T, Kawahara A, Fujii H, Nakagawa Y, Minami Y. 71.  et al. 1994. Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science 266:51871045–47 [Google Scholar]
  72. O'Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A. 72.  2013. Janus kinase inhibitors in autoimmune diseases. Ann. Rheum. Dis. 72:Suppl. 2ii111–15 [Google Scholar]
  73. O'Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A. 73.  2015. The JAK-STAT pathway: impact on human disease and therapeutic intervention. Annu. Rev. Med. 66:311–28 [Google Scholar]
  74. Macchi P, Villa A, Giliani S, Sacco MG, Frattini A. 74.  et al. 1995. Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 377:654465–68 [Google Scholar]
  75. Haan C, Rolvering C, Raulf F, Kapp M, Drückes P. 75.  et al. 2011. Jak1 has a dominant role over Jak3 in signal transduction through γc-containing cytokine receptors. Chem. Biol. 18:3314–23 [Google Scholar]
  76. Beadling C, Guschin D, Witthuhn BA, Ziemiecki A, Ihle JN. 76.  et al. 1994. Activation of JAK kinases and STAT proteins by interleukin-2 and interferon alpha, but not the T cell antigen receptor, in human T lymphocytes. EMBO J 13:235605–15 [Google Scholar]
  77. Johnston JA, Bacon CM, Finbloom DS, Rees RC, Kaplan D. 77.  et al. 1995. Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15. PNAS 92:198705–9 [Google Scholar]
  78. Beadling C, Ng J, Babbage JW, Cantrell DA. 78.  1996. Interleukin-2 activation of STAT5 requires the convergent action of tyrosine kinases and a serine/threonine kinase pathway distinct from the Raf1/ERK2 MAP kinase pathway. EMBO J 15:81902–13 [Google Scholar]
  79. Clark DE, Williams CC, Duplessis TT, Moring KL, Notwick AR. 79.  et al. 2005. ERBB4/HER4 potentiates STAT5A transcriptional activity by regulating novel STAT5A serine phosphorylation events. J. Biol. Chem. 280:2524175–80 [Google Scholar]
  80. Ng J, Cantrell D. 80.  1997. STAT3 is a serine kinase target in T lymphocytes: Interleukin 2 and T cell antigen receptor signals converge upon serine 727. J. Biol. Chem. 272:3924542–49 [Google Scholar]
  81. Lin JX, Leonard WJ. 81.  2000. The role of Stat5a and Stat5b in signaling by IL-2 family cytokines. Oncogene 19:212566–76 [Google Scholar]
  82. Malek TR, Castro I. 82.  2010. Interleukin-2 receptor signaling: at the interface between tolerance and immunity. Immunity 33:2153–65 [Google Scholar]
  83. Owen DL, Farrar MA. 83.  2017. STAT5 and CD4+ T cell immunity. F1000Research 6:32 [Google Scholar]
  84. Snow JW, Abraham N, Ma MC, Herndier BG, Pastuszak AW, Goldsmith MA. 84.  2003. Loss of tolerance and autoimmunity affecting multiple organs in STAT5A/5B-deficient mice. J. Immunol. 171:105042–50 [Google Scholar]
  85. Yao Z, Kanno Y, Kerenyi M, Stephens G, Durant L. 85.  et al. 2007. Nonredundant roles for Stat5a/b in directly regulating Foxp3. Blood 109:104368–75 [Google Scholar]
  86. Burchill MA, Yang J, Vogtenhuber C, Blazar BR, Farrar MA. 86.  2007. IL-2 receptor β-dependent STAT5 activation is required for the development of Foxp3+ regulatory T cells. J. Immunol. 178:1280–90 [Google Scholar]
  87. Moriggl R, Topham DJ, Teglund S, Sexl V, McKay C. 87.  et al. 1999. Stat5 is required for IL-2-induced cell cycle progression of peripheral T cells. Immunity 10:2249–59 [Google Scholar]
  88. Cleary A, Nadeau K, Tu W, Hwa V, Dionis KY. 88.  et al. 2005. Decreased generation and function of CD4+CD25hi T regulatory cells in human STAT5b deficiency. Blood 106:11768 (Abstr.) [Google Scholar]
  89. Cohen AC, Nadeau KC, Tu W, Hwa V, Dionis K. 89.  et al. 2006. Cutting edge: Decreased accumulation and regulatory function of CD4+ CD25high T cells in human STAT5b deficiency. J. Immunol. 177:52770–74 [Google Scholar]
  90. Kanai T, Seki S, Jenks JA, Kohli A, Kawli T. 90.  et al. 2014. Identification of STAT5A and STAT5B target genes in human T cells. PLOS ONE 9:1e86790 [Google Scholar]
  91. Rani A, Afzali B, Kelly A, Tewolde-Berhan L, Hackett M. 91.  et al. 2011. IL-2 regulates expression of C-MAF in human CD4 T cells. J. Immunol. 187:73721–29 [Google Scholar]
  92. Basham B, Sathe M, Grein J, McClanahan T, D'Andrea A. 92.  et al. 2008. In vivo identification of novel STAT5 target genes. Nucleic Acids Res 36:113802–18 [Google Scholar]
  93. Walker SR, Nelson EA, Frank DA. 93.  2007. STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas. Oncogene 26:2224–33 [Google Scholar]
  94. Villarino A, Laurence A, Robinson GW, Bonelli M, Dema B. 94.  et al. 2016. Signal transducer and activator of transcription 5 (STAT5) paralog dose governs T cell effector and regulatory functions. eLife 5:e08384 [Google Scholar]
  95. Hand TW, Cui W, Jung YW, Sefik E, Joshi NS. 95.  et al. 2010. Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival. PNAS 107:3816601–6 [Google Scholar]
  96. Ravichandran KS, Burakoff SJ. 96.  1994. The adapter protein Shc interacts with the interleukin-2 (IL-2) receptor upon IL-2 stimulation. J. Biol. Chem. 269:31599–1602 [Google Scholar]
  97. Reif K, Buday L, Downward J, Cantrell DA. 97.  1994. SH3 domains of the adapter molecule Grb2 complex with two proteins in T cells: the guanine nucleotide exchange protein Sos and a 75-kDa protein that is a substrate for T cell antigen receptor-activated tyrosine kinases. J. Biol. Chem. 269:1914081–87 [Google Scholar]
  98. Saxton RA, Sabatini DM. 98.  2017. mTOR signaling in growth, metabolism, and disease. Cell 168:6960–76 [Google Scholar]
  99. Delgoffe GM, Kole TP, Zheng Y, Zarek PE, Matthews KL. 99.  et al. 2009. The mTOR kinase differentially regulates effector and regulatory T cell lineage commitment. Immunity 30:6832–44 [Google Scholar]
  100. Delgoffe GM, Pollizzi KN, Waickman AT, Heikamp E, Meyers DJ. 100.  et al. 2011. The kinase mTOR regulates the differentiation of helper T cells through the selective activation of signaling by mTORC1 and mTORC2. Nat. Immunol. 12:4295–303 [Google Scholar]
  101. Lee K, Gudapati P, Dragovic S, Spencer C, Joyce S. 101.  et al. 2010. Mammalian target of rapamycin protein complex 2 regulates differentiation of Th1 and Th2 cell subsets via distinct signaling pathways. Immunity 32:6743–53 [Google Scholar]
  102. Powell JD, Pollizzi KN, Heikamp EB, Horton MR. 102.  2012. Regulation of immune responses by mTOR. Annu. Rev. Immunol. 30:139–68 [Google Scholar]
  103. Sinclair LV, Finlay D, Feijoo C, Cornish GH, Gray A. 103.  et al. 2008. Phosphatidylinositol-3-OH kinase and nutrient-sensing mTOR pathways control T lymphocyte trafficking. Nat. Immunol. 9:5513–21 [Google Scholar]
  104. Rolf J, Zarrouk M, Finlay DK, Foretz M, Viollet B, Cantrell DA. 104.  2013. AMPKα1: a glucose sensor that controls CD8 T-cell memory. Eur. J. Immunol. 43:4889–96 [Google Scholar]
  105. Hardie DG. 105.  2014. AMPK—sensing energy while talking to other signaling pathways. Cell Metab 20:6939–52 [Google Scholar]
  106. Osinalde N, Moss H, Arrizabalaga O, Omaetxebarria MJ, Blagoev B. 106.  et al. 2011. Interleukin-2 signaling pathway analysis by quantitative phosphoproteomics. J. Proteom. 75:1177–91 [Google Scholar]
  107. Osinalde N, Sanchez-Quiles V, Akimov V, Blagoev B, Kratchmarova I. 107.  2015. SILAC-based quantification of changes in protein tyrosine phosphorylation induced by interleukin-2 (IL-2) and IL-15 in T-lymphocytes. Data Brief 5:53–58 [Google Scholar]
  108. Osinalde N, Sanchez-Quiles V, Akimov V, Guerra B, Blagoev B, Kratchmarova I. 108.  2015. Simultaneous dissection and comparison of IL-2 and IL-15 signaling pathways by global quantitative phosphoproteomics. Proteomics 15:2–3520–31 [Google Scholar]
  109. Osinalde N, Mitxelena J, Sanchez-Quiles V, Akimov V, Aloria K. 109.  et al. 2016. Nuclear phosphoproteomic screen uncovers ACLY as mediator of IL-2-induced proliferation of CD4+ T lymphocytes. Mol. Cell. Proteom. 15:62076–92 [Google Scholar]
  110. Arneja A, Johnson H, Gabrovsek L, Lauffenburger DA, White FM. 110.  2014. Qualitatively different T cell phenotypic responses to IL-2 versus IL-15 are unified by identical dependences on receptor signal strength and duration. J. Immunol. 192:1123–35 [Google Scholar]
  111. Arnaud M, Mzali R, Gesbert F, Crouin C, Guenzi C. 111.  et al. 2004. Interaction of the tyrosine phosphatase SHP-2 with Gab2 regulates Rho-dependent activation of the c-fos serum response element by interleukin-2. Biochem. J. 382:Pt 2545–56 [Google Scholar]
  112. Adachi M, Ishino M, Torigoe T, Minami Y, Matozaki T. 112.  et al. 1997. Interleukin-2 induces tyrosine phosphorylation of SHP-2 through IL-2 receptor beta chain. Oncogene 14:131629–33 [Google Scholar]
  113. Lu W, Gong D, Bar-Sagi D, Cole PA. 113.  2001. Site-specific incorporation of a phosphotyrosine mimetic reveals a role for tyrosine phosphorylation of SHP-2 in cell signaling. Mol. Cell. 8:4759–69 [Google Scholar]
  114. Gadina M, Stancato LM, Bacon CM, Larner AC, O'Shea JJ. 114.  1998. Involvement of SHP-2 in multiple aspects of IL-2 signaling: evidence for a positive regulatory role. J. Immunol. 160:104657–61 [Google Scholar]
  115. Migone TS, Cacalano NA, Taylor N, Yi T, Waldmann TA, Johnston JA. 115.  1998. Recruitment of SH2-containing protein tyrosine phosphatase SHP-1 to the interleukin 2 receptor; loss of SHP-1 expression in human T-lymphotropic virus type I-transformed T cells. PNAS 95:73845–50 [Google Scholar]
  116. Linossi EM, Babon JJ, Hilton DJ, Nicholson SE. 116.  2013. Suppression of cytokine signaling: the SOCS perspective. Cytokine Growth Factor Rev 24:3241–48 [Google Scholar]
  117. Lucas CL, Chandra A, Nejentsev S, Condliffe AM, Okkenhaug K. 117.  2016. PI3Kδ and primary immunodeficiencies. Nat. Rev. Immunol. 16:11702–14 [Google Scholar]
  118. Cantrell DA. 118.  2001. Phosphoinositide 3-kinase signalling pathways. J. Cell. Sci. 114:Part 81439–45 [Google Scholar]
  119. Milburn CC, Deak M, Kelly SM, Price NC, Alessi DR, Van Aalten DMF. 119.  2003. Binding of phosphatidylinositol. 3: ,4,5-trisphosphate to the pleckstrin homology domain of protein kinase B induces a conformational change. Biochem. J. 375:Part 3531–38 [Google Scholar]
  120. Pearce LR, Komander D, Alessi DR. 120.  2010. The nuts and bolts of AGC protein kinases. Nat. Rev. Mol. Cell Biol. 11:19–22 [Google Scholar]
  121. Macintyre AN, Finlay D, Preston G, Sinclair LV, Waugh CM. 121.  et al. 2011. Protein kinase B controls transcriptional programs that direct cytotoxic T cell fate but is dispensable for T cell metabolism. Immunity 34:2224–36 [Google Scholar]
  122. Hedrick SM, Hess Michelini R, Doedens AL, Goldrath AW, Stone EL. 122.  2012. FOXO transcription factors throughout T cell biology. Nat. Rev. Immunol. 12:9649–61 [Google Scholar]
  123. Hess Michelini R, Doedens AL, Goldrath AW, Hedrick SM. 123.  2013. Differentiation of CD8 memory T cells depends on Foxo1. J. Exp. Med. 210:61189–1200 [Google Scholar]
  124. Waugh C, Sinclair L, Finlay D, Bayascas JR, Cantrell D. 124.  2009. Phosphoinositide (3,4,5)-triphosphate binding to phosphoinositide-dependent kinase 1 regulates a protein kinase B/Akt signaling threshold that dictates T-cell migration, not proliferation. Mol. Cell. Biol. 29:215952–62 [Google Scholar]
  125. Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK. 125.  et al. 2014. 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. 15:188–97 [Google Scholar]
  126. Angulo I, Vadas O, Garçon F, Banham-Hall E, Plagnol V. 126.  et al. 2013. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science 342:6160866–71 [Google Scholar]
  127. Okkenhaug K, Ali K, Vanhaesebroeck B. 127.  2007. Antigen receptor signalling: a distinctive role for the p110δ isoform of PI3K. Trends Immunol 28:280–87 [Google Scholar]
  128. Ward SG, Cantrell DA. 128.  2001. Phosphoinositide 3-kinases in T lymphocyte activation. Curr. Opin. Immunol. 13:3332–38 [Google Scholar]
  129. Truitt KE, Mills GB, Turck CW, Imboden JB. 129.  1994. SH2-dependent association of phosphatidylinositol 3′-kinase 85-kDa regulatory subunit with the interleukin-2 receptor β chain. J. Biol. Chem. 269:85937–43 [Google Scholar]
  130. Migone TS, Rodig S, Cacalano NA, Berg M, Schreiber RD, Leonard WJ. 130.  1998. Functional cooperation of the interleukin-2 receptor beta chain and Jak1 in phosphatidylinositol 3-kinase recruitment and phosphorylation. Mol. Cell. Biol. 18:116416–22 [Google Scholar]
  131. Gu H, Maeda H, Moon JJ, Lord JD, Yoakim M. 131.  et al. 2000. New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway. Mol. Cell. Biol. 20:197109–20 [Google Scholar]
  132. Monfar M, Lemon KP, Grammer TC, Cheatham L, Chung J. 132.  et al. 1995. Activation of pp70/85 S6 kinases in interleukin-2-responsive lymphoid cells is mediated by phosphatidylinositol 3-kinase and inhibited by cyclic AMP. Mol. Cell. Biol. 15:1326–37 [Google Scholar]
  133. Stahl M, Dijkers PF, Kops GJPL, Lens SMA, Coffer PJ. 133.  et al. 2002. The forkhead transcription factor FoxO regulates transcription of p27Kip1 and Bim in response to IL-2. J. Immunol. 168:105024–31 [Google Scholar]
  134. Brunn GJ, Williams J, Sabers C, Wiederrecht G, Lawrence JC, Abraham RT. 134.  1996. Direct inhibition of the signaling functions of the mammalian target of rapamycin by the phosphoinositide 3-kinase inhibitors, wortmannin and LY294002. EMBO J 15:195256–67 [Google Scholar]
  135. Jacobs MD, Black J, Futer O, Swenson L, Hare B. 135.  et al. 2005. Pim-1 ligand-bound structures reveal the mechanism of serine/threonine kinase inhibition by LY294002. J. Biol. Chem. 280:1413728–34 [Google Scholar]
  136. Najafov A, Shpiro N, Alessi DR. 136.  2012. Akt is efficiently activated by PIF-pocket- and PtdIns(3,4,5)P3-dependent mechanisms leading to resistance to PDK1 inhibitors. Biochem. J. 448:2285–95 [Google Scholar]
  137. Clark J, Anderson KE, Juvin V, Smith TS, Karpe F. 137.  et al. 2011. Quantification of PtdInsP3 molecular species in cells and tissues by mass spectrometry. Nat. Methods 8:3267–72 [Google Scholar]
  138. Costello PS, Gallagher M, Cantrell DA. 138.  2002. Sustained and dynamic inositol lipid metabolism inside and outside the immunological synapse. Nat. Immunol. 3:111082–89 [Google Scholar]
  139. Fabre S, Lang V, Harriague J, Jobart A, Unterman TG. 139.  et al. 2005. 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. 174:74161–71 [Google Scholar]
  140. Wu W-I, Voegtli WC, Sturgis HL, Dizon FP, Vigers GPA, Brandhuber BJ. 140.  2010. Crystal structure of human AKT1 with an allosteric inhibitor reveals a new mode of kinase inhibition. PLOS ONE 5:9e12913 [Google Scholar]
  141. Grzes KM, Swamy M, Hukelmann JL, Emslie E, Sinclair LV, Cantrell DA. 141.  2017. Control of amino acid transport coordinates metabolic reprogramming in T-cell malignancy. Leukemia 31:2771–79 [Google Scholar]
  142. Nika K, Soldani C, Salek M, Paster W, Gray A. 142.  et al. 2010. Constitutively active Lck kinase in T cells drives antigen receptor signal transduction. Immunity 32:6766–77 [Google Scholar]
  143. Bensinger SJ, Walsh PT, Zhang J, Carroll M, Parsons R. 143.  et al. 2004. Distinct IL-2 receptor signaling pattern in CD4+CD25+ regulatory T cells. J. Immunol. 172:95287–96 [Google Scholar]
  144. Preston GC, Sinclair LV, Kaskar A, Hukelmann JL, Navarro MN. 144.  et al. 2015. Single cell tuning of Myc expression by antigen receptor signal strength and interleukin-2 in T lymphocytes. EMBO J 34:152008–24 [Google Scholar]
  145. Navarro MN, Goebel J, Feijoo-Carnero C, Morrice N, Cantrell DA. 145.  2011. Phosphoproteomic analysis reveals an intrinsic pathway for the regulation of histone deacetylase 7 that controls the function of cytotoxic T lymphocytes. Nat. Immunol. 12:4352–61 [Google Scholar]
  146. Oyler-Yaniv A, Oyler-Yaniv J, Whitlock BM, Liu Z, Germain RN. 146.  et al. 2017. A tunable diffusion-consumption mechanism of cytokine propagation enables plasticity in cell-to-cell communication in the immune system. Immunity 46:4609–20 [Google Scholar]
  147. Cantrell DA, Smith KA. 147.  1984. The interleukin-2 T-cell system: a new cell growth model. Science 224:46551312–16 [Google Scholar]
  148. Smith KA. 148.  2004. The quantal theory of how the immune system discriminates between “self and non-self. .” Med. Immunol. 3:13 [Google Scholar]
  149. Smith KA. 149.  2006. The structure of IL2 bound to the three chains of the IL2 receptor and how signaling occurs. Med. Immunol. 5:3 [Google Scholar]
  150. Smith KA. 150.  2006. The quantal theory of immunity. Cell Res 16:111–19 [Google Scholar]
  151. Zeiser R, Leveson-Gower DB, Zambricki EA, Kambham N, Beilhack A. 151.  et al. 2007. Differential impact of mammalian target of rapamycin inhibition on CD4+CD25+Foxp3+ regulatory T cells compared with conventional CD4+ T cells. Blood 111:1453–62 [Google Scholar]
  152. Levine AG, Arvey A, Jin W, Rudensky AY. 152.  2014. Continuous requirement for the TCR in regulatory T cell function. Nat. Immunol. 15:111070–78 [Google Scholar]
  153. Vahl JC, Drees C, Heger K, Heink S, Fischer JC. 153.  et al. 2014. Continuous T cell receptor signals maintain a functional regulatory T cell pool. Immunity 41:5722–36 [Google Scholar]
  154. Kuwabara T, Kasai H, Kondo M. 154.  2016. Acetylation modulates IL-2 receptor signaling in T cells. J. Immunol. 197:114334–43 [Google Scholar]
  155. Swamy M, Pathak S, Grzes KM, Damerow S, Sinclair LV. 155.  et al. 2016. Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy. Nat. Immunol. 17:6712–20 [Google Scholar]
  156. Ivan M, Kaelin WG. 156.  2017. The EGLN-HIF O2-sensing system: multiple inputs and feedbacks. Mol. Cell. 66:6772–79 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error