Transmembrane Signals Mediated by IL-2 and IL-15 Control the Life and Death of Lymphocytes

  • Thomas A. Waldmann
  • Sigrid Dubois
  • Jürgen Müller
  • Carolyn Goldman
  • Sándor Damjanovich
Part of the Springer Series in Biophysics book series (BIOPHYSICS, volume 8)


Natural Killer Cell Receptor Subunit Transmembrane Signal Severe Combine Immune Deficiency Receptor Gamma Chain 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Aman MJ, Migone TS, Sasaki A, Ascherman DP, Zhu M, Soldaini E, Imada K, Miyajima A, Yoshimura A, Leonard WJ (1999) CIS associates with the interleukin-2 receptor beta chain and inhibits interleukin-2-dependent signaling. J Biol Chem 274:30266–30272CrossRefPubMedGoogle Scholar
  2. Anderson DM, Kumaki S, Ahdieh M, Bertles J, Tometsko M, Loomis A, Giri J, Copeland NG, Gilbert DJ, Jenkins NA, Valentine V, Shapiro DN, Morris SW, Park LS, Cosman D (1995) Functional characterization of the human interleukin-15 receptor alpha chain and close linkage of IL15RA and IL2RA genes. J Biol Chem 270:29862–29869CrossRefPubMedGoogle Scholar
  3. Armitage RJ, Macduff BM, Eisenman J, Paxton R, Grabstein KH (1995) IL-15 has stimulatory activity for the induction of B cell proliferation and differentiation. J Immunol 154:483–490PubMedGoogle Scholar
  4. Azimi N, Jacobson S, Leist T, Waldmann TA (1999) Involvement of IL-15 in the pathogenesis of human T lymphotropic virus type I-associated myelopathy/tropical spastic paraparesis: implications for therapy with a monoclonal antibody directed to the IL-2/15R beta receptor. J Immunol 163:4064–4072PubMedGoogle Scholar
  5. Azimi N, Nagai M, Jacobson S, Waldmann TA (2001) IL-15 plays a major role in the persistence of Tax-specific CD8 cells in HAM/TSP patients. Proc Natl Acad Sci USA 98:14559–14564CrossRefPubMedGoogle Scholar
  6. Bamford RN, Grant AJ, Burton JD, Peters C, Kurys G, Goldman CK, Brennan J, Roessler E, Waldmann TA (1994) The interleukin (IL) 2 receptor beta chain is shared by IL-2 and a cytokine, provisionally designated IL-T, that stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc Natl Acad Sci USA 91:4940–4944PubMedGoogle Scholar
  7. Baslund B, Tvede N, Danneskiold-Samsoe B, Petersen J, Petersen LJ, Schuurman J, de Winkel JV, Larsson P, Panayi G, McInnes LB (2003) A novel human monoclonal antibody against IL-15 (humax-IL15) in patients with active rheumatoid arthritis (RA): results of a double-blind, placebo-controlled phase I/II trial. Arthritis Rheumatism 48(Suppl S):1706Google Scholar
  8. Bazan JF (1990) Structural design and molecular evolution of a cytokine receptor superfamily. Proc Natl Acad Sci USA 87:6934–6938PubMedGoogle Scholar
  9. Bielekova B, Richert N, Howard T, Blevins G, Markovic-Plese S, McCartin J, Wurfel J, Ohayon J, Waldmann TA, McFarland HF, Martin R (2004) Humanized anti-CD25 (daclizumab) inhibits disease activity in multiple sclerosis patients failing to respond to interferon beta. Proc Natl Acad Sci USA 101:8705–8708CrossRefPubMedGoogle Scholar
  10. Brennan P, Babbage JW, Burgering BM, Groner B, Reif K, Cantrell DA (1997) Phosphatidylinositol 3-kinase couples the interleukin-2 receptor to the cell cycle regulator E2F. Immunity 7:679–689CrossRefPubMedGoogle Scholar
  11. Bulanova E, Budagian V, Pohl T, Krause H, Durkop H, Paus R, Bulfone-Paus S (2001) The IL-15R alpha chain signals through association with Syk in human B cells. J Immunol 167:6292–6302PubMedGoogle Scholar
  12. Bulfone-Pau SS, Bulanova E, Pohl T, Budagian V, Durkop H, Ruckert R, Kunzendorf U, Paus R, Krause H (1999) Death deflected: IL-15 inhibits TNF-alpha-mediated apoptosis in fibroblasts by TRAF2 recruitment to the IL-15Ralpha chain. FASEB J 13:1575–1585PubMedGoogle Scholar
  13. Burkett PR, Koka R, Chien M, Chai S, Chan F, Ma A, Boone DL (2003) IL-15R alpha expression on CD8+ T cells is dispensable for T cell memory. Proc Natl Acad Sci USA 100:4724–4729CrossRefPubMedGoogle Scholar
  14. Burton JD, Bamford RN, Peters C, Grant AJ, Kurys G, Goldman CK, Brennan J, Roessler E, Waldmann TA (1994) A lymphokine, provisionally designated interleukin T and produced by a human adult T-cell leukemia line, stimulates T-cell proliferation and the induction of lymphokine-activated killer cells. Proc Natl Acad Sci USA 91:4935–4939PubMedGoogle Scholar
  15. Cao X, Kozak CA, Liu YJ, Noguchi M, O’Connell E, Leonard WJ (1993) Characterization of cDNAs encoding the murine interleukin 2 receptor (IL-2R) gamma chain: chromosomal mapping and tissue specificity of IL-2R gamma chain expression. Proc Natl Acad Sci USA 90:8464–8468PubMedGoogle Scholar
  16. Cao X, Shores EW, Hu-Li J, Anver MR, Kelsall BL, Russell SM, Drago J, Noguchi M, Grinberg A, Bloom ET, Paul WE, Katz SI, Love PE, Leonard WJ (1995) Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity 2:223–238CrossRefPubMedGoogle Scholar
  17. Carson WE, Giri JG, Lindemann MJ, Linett ML, Ahdieh M, Paxton R, Anderson D, Eisenmann J, Grabstein K, Caligiuri MA (1994) Interleukin (IL) 15 is a novel cytokine that activates human natural killer cells via components of the IL-2 receptor. J Exp Med 180:1395–1403CrossRefPubMedGoogle Scholar
  18. Cheng EH, Kirsch DG, Clem RJ, Ravi R, Kastan MB, Bedi A, Ueno K, Hardwick JM (1997) Conversion of Bcl-2 to a Bax-like death effector by caspases. Science 278:1966–1968CrossRefPubMedGoogle Scholar
  19. Cosman D, Cerretti DP, Larsen A, Park L, March C, Dower S, Gillis S, Urdal D (1984) Cloning, sequence and expression of human interleukin-2 receptor. Nature 312:768–771CrossRefPubMedGoogle Scholar
  20. Crawley JB, Rawlinson L, Lali FV, Page TH, Saklatvala J, Foxwell BM (1997) T cell proliferation in response to interleukins 2 and 7 requires p38MAP kinase activation. J Biol Chem 272:15023–15027CrossRefPubMedGoogle Scholar
  21. Curtin JF, Cotter TG (2003) Live and let die: regulatory mechanisms in Fas-mediated apoptosis. Cell Signal 15:983–992CrossRefPubMedGoogle Scholar
  22. Damjanovich S, Bene L, Matko J, Alileche A, Goldman CK, Sharrow S, Waldmann TA (1997) Preassembly of interleukin 2 (IL-2) receptor subunits on resting Kit 225 K6 T cells and their modulation by IL-2, IL-7, and IL-15: a fluorescence resonance energy transfer study. Proc Natl Acad Sci USA 94:13134–13139CrossRefPubMedGoogle Scholar
  23. DiSanto JP, Muller W, Guy-Grand D, Fischer A, Rajewsky K (1995) Lymphoid development in mice with a targeted deletion of the interleukin 2 receptor gamma chain. Proc Natl Acad Sci USA 92:377–381PubMedGoogle Scholar
  24. Dooms H, Desmedt M, Vancaeneghem S, Rottiers P, Goossens V, Fiers W, Grooten J (1998) Quiescence-inducing and antiapoptotic activities of IL-15 enhance secondary CD4+ T cell responsiveness to antigen. J Immunol 161:2141–2150PubMedGoogle Scholar
  25. Dubois S, Mariner J, Waldmann TA, Tagaya Y (2002) IL-15Ralpha recycles and presents IL-15 in trans to neighboring cells. Immunity 17:537–547CrossRefPubMedGoogle Scholar
  26. Dubois S, Shou W, Haneline LS, Fleischer S, Waldmann TA, Muller JR (2003) Distinct pathways involving the FK506-binding proteins 12 and 12.6 underlie IL-2-versus IL-15-mediated proliferation of T cells. Proc Natl Acad Sci USA 100:14169–14174CrossRefPubMedGoogle Scholar
  27. Dumont FJ (2000) FK506, an immunosuppressant targeting calcineurin function. Curr Med Chem 7:731–748PubMedGoogle Scholar
  28. Edelbaum D, Mohamadzadeh M, Bergstresser PR, Sugamura K, Takashima A (1995) Interleukin (IL)-15 promotes the growth of murine epidermal gamma delta T cells by a mechanism involving the beta-and gamma c-chains of the IL-2 receptor. J Invest Dermatol 105:837–843CrossRefPubMedGoogle Scholar
  29. Ellery JM, Nicholls PJ (2002) Alternate signalling pathways from the interleukin-2 receptor. Cytokine Growth Factor Rev 13:27–40CrossRefPubMedGoogle Scholar
  30. Evans GA, Goldsmith MA, Johnston JA, Xu W, Weiler SR, Erwin R, Howard OM, Abraham RT, O’shea JJ, Greene WC, Farrar WL (1995) Analysis of interleukin-2-dependent signal transduction through the Shc/Grb2 adapter pathway. Interleukin-2-dependent mitogenesis does not require Shc phosphorylation or receptor association. J Biol Chem 270:28858–28863CrossRefPubMedGoogle Scholar
  31. Friedmann MC, Migone TS, Russell SM, Leonard WJ (1996) Different interleukin 2 receptor beta-chain tyrosines couple to at least two signaling pathways and synergistically mediate interleukin 2-induced proliferation. Proc Natl Acad Sci USA 93:2077–2082CrossRefPubMedGoogle Scholar
  32. Fujii H, Ogasawara K, Otsuka H, Suzuki M, Yamamura K, Yokochi T, Miyazaki T, Suzuki H, Mak TW, Taki S, Taniguchi T (1998) Functional dissection of the cytoplasmic subregions of the IL-2 receptor beta chain in primary lymphocyte populations. Embo J 17:6551–6557CrossRefPubMedGoogle Scholar
  33. Gaffen SL (2001) Signaling domains of the interleukin 2 receptor. Cytokine 14:63–77CrossRefPubMedGoogle Scholar
  34. Gaffen SL, Lai SY, Ha M, Liu X, Hennighausen L, Greene WC, Goldsmith MA (1996) Distinct tyrosine residues within the interleukin-2 receptor beta chain drive signal transduction specificity, redundancy, and diversity. J Biol Chem 271:21381–21390CrossRefPubMedGoogle Scholar
  35. Garcia VE, Jullien D, Song M, Uyemura K, Shuai K, Morita CT, Modlin RL (1998) IL-15 enhances the response of human gamma delta T cells to nonpeptide [correction of nonpetide] microbial antigens. J Immunol 160:4322–4329PubMedGoogle Scholar
  36. Giri JG, Ahdieh M, Eisenman J, Shanebeck K, Grabstein K, Kumaki S, Namen A, Park LS, Cosman D, Anderson D (1994) Utilization of the beta and gamma chains of the IL-2 receptor by the novel cytokine IL-15. EMBO J 13:2822–2830PubMedGoogle Scholar
  37. Giri JG, Kumaki S, Ahdieh M, Friend DJ, Loomis A, Shanebeck K, DuBose R, Cosman D, Park LS, Anderson DM (1995) Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor. EMBO J 14:3654–3663PubMedGoogle Scholar
  38. Goldsmith MA, Lai SY, Xu W, Amaral MC, Kuczek ES, Parent LJ, Mills GB, Tarr KL, Longmore GD, Greene WC (1995) Growth signal transduction by the human interleukin-2 receptor requires cytoplasmic tyrosines of the beta chain and non-tyrosine residues of the gamma c chain. J Biol Chem 270:21729–21737CrossRefPubMedGoogle Scholar
  39. Grabstein KH, Eisenman J, Shanebeck K, Rauch C, Srinivasan S, Fung V, Beers C, Richardson J, Schoenborn MA, Ahdieh M, Johnson L, Alderson MR, Watson JD, Anderson DM, Giri JG (1994) Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science 264:965–968PubMedGoogle Scholar
  40. Grant AJ, Roessler E, Ju G, Tsudo M, Sugamura K, Waldmann TA (1992) The interleukin 2 receptor (IL-2R): the IL-2R alpha subunit alters the function of the IL-2R beta subunit to enhance IL-2 binding and signaling by mechanisms that do not require binding of IL-2 to IL-2R alpha subunit. Proc Natl Acad Sci USA 89:2165–2169PubMedGoogle Scholar
  41. Green DR, Droin N, Pinkoski M (2003) Activation-induced cell death in T cells. Immunol Rev 193:70–81CrossRefPubMedGoogle Scholar
  42. Guex-Crosier Y, Raber J, Chan CC, Kriete MS, Benichou J, Pilson RS, Kerwin JA, Waldmann TA, Hakimi J, Roberge FG (1997) Humanized antibodies against the alpha-chain of the IL-2 receptor and against the beta-chain shared by the IL-2 and IL-15 receptors in a monkey uveitis model of autoimmune diseases. J Immunol 158:452–458PubMedGoogle Scholar
  43. Hakimi J, Ha VC, Lin P, Campbell E, Gately MK, Tsudo M, Payne PW, Waldmann TA, Grant AJ, Tsien WH (1993) Humanized Mik beta 1, a humanized antibody to the IL-2 receptor beta-chain that acts synergistically with humanized anti-TAC. J Immunol 151:1075–1085PubMedGoogle Scholar
  44. Hatakeyama M, Mori H, Doi T, Taniguchi T (1989a) A restricted cytoplasmic region of IL-2 receptor beta chain is essential for growth signal transduction but not for ligand binding and internalization. Cell 59:837–845CrossRefPubMedGoogle Scholar
  45. Hatakeyama M, Tsudo M, Minamoto S, Kono T, Doi T, Miyata T, Miyasaka M, Taniguchi T (1989b) Interleukin-2 receptor beta chain gene: generation of three receptor forms by cloned human alpha and beta chain cDNAs. Science 244:551–556PubMedGoogle Scholar
  46. Hatakeyama M, Kono T, Kobayashi N, Kawahara A, Levin SD, Perlmutter RM, Taniguchi T (1991) Interaction of the IL-2 receptor with the src-family kinase p56lck: identification of novel intermolecular association. Science 252:1523–1528PubMedGoogle Scholar
  47. Hodge MR, Ranger AM, Charles de la Brousse F, Hoey T, Grusby MJ, Glimcher LH (1996) Hyperproliferation and dysregulation of IL-4 expression in NF-ATP-deficient mice. Immunity 4:397–405CrossRefPubMedGoogle Scholar
  48. Johnston JA, Bacon CM, Finbloom DS, Rees RC, Kaplan D, Shibuya K, Ortaldo JR, Gupta S, Chen YQ, Giri JD, O’shea JJ (1995) Tyrosine phosphorylation and activation of STAT5, STAT3, and Janus kinases by interleukins 2 and 15. Proc Natl Acad Sci USA 92:8705–8709PubMedGoogle Scholar
  49. Kataoka T, Budd RC, Holler N, Thome M, Martinon F, Irmler M, Burns K, Hahne M, Kennedy N, Kovacsovics M, Tschopp J (2000) The caspase-8 inhibitor FLIP promotes activation of NF-kappaB and Erk signaling pathways. Curr Biol 10:640–648CrossRefPubMedGoogle Scholar
  50. Kennedy MK, Park LS (1996) Characterization of interleukin-15 (IL-15) and the IL-15 receptor complex. J Clin Immunol 16:134–143CrossRefPubMedGoogle Scholar
  51. Kennedy MK, Glaccum M, Brown SN, Butz EA, Viney JL, Embers M, Matsuki N, Charrier K, Sedger L, Willis CR, Brasel K, Morrissey PJ, Stocking K, Schuh JC, Joyce S, Peschon JJ (2000) Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med 191:771–780CrossRefPubMedGoogle Scholar
  52. Kim YS, Maslinski W, Zheng XX, Stevens AC, Li XC, Tesch GH, Kelley VR, Strom TB (1998) Targeting the IL-15 receptor with an antagonist IL-15 mutant/Fc gamma2a protein blocks delayed-type hypersensitivity. J Immunol 160:5742–5748PubMedGoogle Scholar
  53. Kneitz B, Herrmann T, Yonehara S, Schimpl A (1995) Normal clonal expansion but impaired Fas-mediated cell death and anergy induction in interleukin-2-deficient mice. Eur J Immunol 25:2572–2577PubMedGoogle Scholar
  54. Koka R, Burkett PR, Chien M, Chai S, Chan F, Lodolce JP, Boone DL, Ma A (2003) Interleukin (IL)-15R[alpha]-deficient natural killer cells survive in normal but not IL-15R[alpha]-deficient mice. J Exp Med 197:977–984CrossRefPubMedGoogle Scholar
  55. Kondo M, Takeshita T, Ishii N, Nakamura M, Watanabe S, Arai K, Sugamura K (1993) Sharing of the interleukin-2 (IL-2) receptor gamma chain between receptors for IL-2 and IL-4. Science 262:1874–1877PubMedGoogle Scholar
  56. Kovanen PE, Leonard WJ (1999) Inhibitors keep cytokines in check. Curr Biol 9:R899–R902CrossRefPubMedGoogle Scholar
  57. Ku CC, Murakami M, Sakamoto A, Kappler J, Marrack P (2000) Control of homeostasis of CD8+ memory T cells by opposing cytokines. Science 288:675–678CrossRefPubMedGoogle Scholar
  58. Kuo CJ, Chung J, Fiorentino DF, Flanagan WM, Blenis J, Crabtree GR (1992) Rapamycin selectively inhibits interleukin-2 activation of p70 S6 kinase. Nature 358:70–73CrossRefPubMedGoogle Scholar
  59. Lenardo MJ (1991) Interleukin-2 programs mouse alpha beta T lymphocytes for apoptosis. Nature 353:858–861CrossRefPubMedGoogle Scholar
  60. Lenardo MJ (1996) Fas and the art of lymphocyte maintenance. J Exp Med 183:721–724CrossRefPubMedGoogle Scholar
  61. Leonard WJ (2000) IL-2 family cytokines and their receptor. Academic Press, San DiegoGoogle Scholar
  62. Leonard WJ, Depper JM, Crabtree GR, Rudikoff S, Pumphrey J, Robb RJ, Kronke M, Svetlik PB, Peffer NJ, Waldmann TA, Greene WC (1984) Molecular cloning and expression of cDNAs for the human interleukin-2 receptor. Nature 311:626–631CrossRefPubMedGoogle Scholar
  63. Leonard WJ, Imada K, Nakajima H, Puel A, Soldaini E, John S (1999) Signaling via the IL-2 and IL-7 receptors from the membrane to the nucleus. Cold Spring Harbor Symp Quant Biol 64:417–424CrossRefPubMedGoogle Scholar
  64. Lin JX, Migone TS, Tsang M, Friedmann M, Weatherbee JA, Zhou L, Yamauchi A, Bloom ET, Mietz J, John S, Leonard WJ (1995) The role of shared receptor motifs and common Stat proteins in the generation of cytokine pleiotropy and redundancy by IL-2, IL-4, IL-7, IL-13, and IL-15. Immunity 2:331–339CrossRefPubMedGoogle Scholar
  65. Lin JX, Mietz J, Modi WS, John S, Leonard WJ (1996) Cloning of human Stat5B. Reconstitution of interleukin-2-induced Stat5A and Stat5B DNA binding activity in COS-7 cells. J Biol Chem 271:10738–10744CrossRefPubMedGoogle Scholar
  66. Lodolce JP, Boone DL, Chai S, Swain RE, Dassopoulos T, Trettin S, Ma A (1998) IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9:669–676CrossRefPubMedGoogle Scholar
  67. Lowenthal JW, Greene WC (1987) Contrasting interleukin 2 binding properties of the alpha (p55) and beta (p70) protein subunits of the human high-affinity interleukin 2 receptor. J Exp Med 166:1156–1161CrossRefPubMedGoogle Scholar
  68. Lucas JA, Miller AT, Atherly LO, Berg LJ (2003) The role of Tec family kinases in T cell development and function. Immunol Rev 191:119–138CrossRefPubMedGoogle Scholar
  69. Lyakh L, Ghosh P, Rice NR (1997) Expression of NFAT-family proteins in normal human T cells. Mol Cell Biol 17:2475–2484PubMedGoogle Scholar
  70. Ma A, Boone DL, Lodolce JP (2000) The pleiotropic functions of interleukin 15: not so interleukin 2-like after all. J Exp Med 191:753–756CrossRefPubMedGoogle Scholar
  71. Macchi P, Villa A, Giliani S, Sacco MG, Frattini A, Porta F, Ugazio AG, Johnston JA, Candotti F, O’shea JJ, Vessoni P, Notarangelo LD (1995) Mutations of Jak-3 gene in patients with autosomal severe combined immune deficiency (SCID). Nature 377:65–68CrossRefPubMedGoogle Scholar
  72. Marine JC, Topham DJ, McKay C, Wang D, Parganas E, Stravopodis D, Yoshimura A, Ihle JN (1999) SOCS1 deficiency causes a lymphocyte-dependent perinatal lethality. Cell 98:609–616CrossRefPubMedGoogle Scholar
  73. Mariner JM, Lantz V, Waldmann TA, Azimi N (2001) Human T cell lymphotropic virus type I Tax activates IL-15R alpha gene expression through an NF-kappa B site. J Immunol 166:2602–2609PubMedGoogle Scholar
  74. Marks-Konczalik J, Dubois S, Losi JM, Sabzevari H, Yamada N, Feigenbaum L, Waldmann TA, Tagaya Y (2000) IL-2-induced activation-induced cell death is inhibited in IL-15 transgenic mice. Proc Natl Acad Sci USA 97:11445–11450CrossRefPubMedGoogle Scholar
  75. McInnes IB, Leung BP, Sturrock RD, Field M, Liew FY (1997) Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha production in rheumatoid arthritis. Nat Med 3:189–195CrossRefPubMedGoogle Scholar
  76. Mention JJ, Ben Ahmed M, Begue B, Barbe U, Verkarre V, Asnafi V, Colombel JF, Cugnenc PH, Ruemmele FM, McIntyre E, Brousse N, Cellier C, Cerf-Bensussan N (2003) Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease. Gastroenterology 125:730–745CrossRefPubMedGoogle Scholar
  77. Miller AT, Berg LJ (2002) Defective Fas ligand expression and activation-induced cell death in the absence of IL-2-inducible T cell kinase. J Immunol 168:2163–2172PubMedGoogle Scholar
  78. Minami Y, Kono T, Miyazaki T, Taniguchi T (1993) The IL-2 receptor complex: its structure, function, and target genes. Annu Rev Immunol 11:245–268CrossRefPubMedGoogle Scholar
  79. Mingari MC, Vitale C, Cantoni C, Bellomo R, Ponte M, Schiavetti F, Bertone S, Moretta A, Moretta L (1997) Interleukin-15-induced maturation of human natural killer cells from early thymic precursors: selective expression of CD94/NKG2-A as the only HLA class I-specific inhibitory receptor. Eur J Immunol 27:1374–1380PubMedGoogle Scholar
  80. Mixter PF, Russell JQ, Budd RC (1994) Delayed kinetics of T lymphocyte anergy and deletion in lpr mice. J Autoimmun 7:697–710CrossRefPubMedGoogle Scholar
  81. Miyazaki T, Kawahara A, Fujii H, Nakagawa Y, Minami Y, Liu ZJ, Oishi I, Silvennoinen O, Witthuhn BA, Ihle JN, Taniguchi T (1994) Functional activation of Jak1 and Jak3 by selective association with IL-2 receptor subunits. Science 266:1045–1047PubMedGoogle Scholar
  82. Morris JC, Waldmann TA (2000) Advances in interleukin 2 receptor targeted treatment. Ann Rheum Dis 59(Suppl 1):109–114CrossRefGoogle Scholar
  83. Mrozek E, Anderson P, Caligiuri MA (1996) Role of interleukin-15 in the development of human CD56+ natural killer cells from CD34+ hematopoietic progenitor cells. Blood 87:2632–2640PubMedGoogle Scholar
  84. Nakamura Y, Russell SM, Mess SA, Friedmann M, Erdos M, Francois C, Jacques Y, Adelstein S, Leonard WJ (1994) Heterodimerization of the IL-2 receptor beta-and gamma-chain cytoplasmic domains is required for signalling. Nature 369:330–333CrossRefPubMedGoogle Scholar
  85. Nashan B, Moore R, Amlot P, Schmidt AG, Abeywickrama K, Soulillou JP (1997) Randomised trial of basiliximab versus placebo for control of acute cellular rejection in renal allograft recipients. CHIB 201 International Study Group. Lancet 350:1193–1198CrossRefPubMedGoogle Scholar
  86. Nelson BH, Lord JD, Greenberg PD (1994) Cytoplasmic domains of the interleukin-2 receptor beta and gamma chains mediate the signal for T-cell proliferation. Nature 369:333–336CrossRefPubMedGoogle Scholar
  87. Nikaido T, Shimizu A, Ishida N, Sabe H, Teshigawara K, Maeda M, Uchiyama T, Yodoi J, Honjo T (1984) Molecular cloning of cDNA encoding human interleukin-2 receptor. Nature 311: 631–635CrossRefPubMedGoogle Scholar
  88. Nishimura Y, Ishii A, Kobayashi Y, Yamasaki Y, Yonehara S (1995) Expression and function of mouse Fas antigen on immature and mature T cells. J Immunol 154:4395–4403PubMedGoogle Scholar
  89. Noguchi M, Nakamura Y, Russell SM, Ziegler SF, Tsang M, Cao X, Leonard WJ (1993) Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor. Science 262:1877–1880PubMedGoogle Scholar
  90. Nosaka T, van Deursen JM, Tripp RA, Thierfelder WE, Witthuhn BA, McMickle AP, Doherty PC, Grosveld GC, Ihle JN (1995) Defective lymphoid development in mice lacking Jak3. Science 270:800–802PubMedGoogle Scholar
  91. Nussenblatt RB, Fortin E, Schiffman R, Rizzo L, Smith J, Van Veldhuisen P, Sran P, Yaffe A, Goldman CK, Waldmann TA, Whitcup SM (1999) Treatment of noninfectious intermediate and posterior uveitis with the humanized anti-Tac mAb: a phase I/II clinical trial. Proc Natl Acad Sci USA 96:7462–7466CrossRefPubMedGoogle Scholar
  92. Ogasawara K, Hida S, Azimi N, Tagaya Y, Sato T, Yokochi-Fukuda T, Waldmann TA, Taniguchi T, Taki S (1998) Requirement for IRF-1 in the microenvironment supporting development of natural killer cells. Nature 391:700–703CrossRefPubMedGoogle Scholar
  93. Oh S, Berzofsky JA, Burke DS, Waldmann TA, Perera LP (2003) Coadministration of HIV vaccine vectors with vaccinia viruses expressing IL-15 but not IL-2 induces long-lasting cellular immunity. Proc Natl Acad Sci USA 100 3392–3397CrossRefPubMedGoogle Scholar
  94. Papiernik M, de Moraes ML, Pontoux C, Vasseur F, Penit C (1998) Regulatory CD4 T cells: expression of IL-2R alpha chain, resistance to clonal deletion and IL-2 dependency. Int Immunol 10:371–378CrossRefPubMedGoogle Scholar
  95. Plaetinck G, Combe MC, Corthesy P, Sperisen P, Kanamori H, Honjo T, Nabholz M (1990) Control of IL-2 receptor-alpha expression by IL-1, tumor necrosis factor, and IL-2. Complex regulation via elements in the 5′ flanking region. J Immunol 145:3340–3347PubMedGoogle Scholar
  96. Puel A, Ziegler SF, Buckley RH, Leonard WJ (1998) Defective IL7R expression in T(−)B(+)NK(+) severe combined immunodeficiency. Nat Genet 20:394–397CrossRefPubMedGoogle Scholar
  97. Ravichandran KS, Burakoff SJ (1994) The adapter protein Shc interacts with the interleukin-2 (IL-2) receptor upon IL-2 stimulation. J Biol Chem 269:1599–1602PubMedGoogle Scholar
  98. Ravichandran KS, Igras V, Shoelson SE, Fesik SW, Burakoff SJ (1996) Evidence for a role for the phosphotyrosine-binding domain of Shc in interleukin 2 signaling. Proc Natl Acad Sci USA 93:5275–5280CrossRefPubMedGoogle Scholar
  99. Remillard B, Petrillo R, Maslinski W, Tsudo M, Strom TB, Cantley L, Varticovski L (1991) Interleukin-2 receptor regulates activation of phosphatidylinositol 3-kinase. J Biol Chem 266:14167–14170PubMedGoogle Scholar
  100. Roessler E, Grant A, Ju G, Tsudo M, Sugamura K, Waldmann TA (1994) Cooperative interactions between the interleukin 2 receptor alpha and beta chains alter the interleukin 2-binding affinity of the receptor subunits. Proc Natl Acad Sci USA 91:3344–3347PubMedGoogle Scholar
  101. Romero F, Martinez AC, Camonis J, Rebollo A (1999) Aiolos transcription factor controls cell death in T cells by regulating Bcl-2 expression and its cellular localization. Embo J 18:3419–3430CrossRefPubMedGoogle Scholar
  102. Rubin LA, Nelson DL (1990) The soluble interleukin-2 receptor: biology, function, and clinical application. Ann Intern Med 113:619–627PubMedGoogle Scholar
  103. Ruchatz H, Leung BP, Wei XQ, McInnes IB, Liew FY (1998) Soluble IL-15 receptor alpha-chain administration prevents murine collagen-induced arthritis: a role for IL-15 in development of antigen-induced immunopathology. J Immunol 160:5654–5660PubMedGoogle Scholar
  104. Russell JH, Wang R (1993) Autoimmune gld mutation uncouples suicide and cytokine/proliferation pathways in activated, mature T cells. Eur J Immunol 23:2379–2382PubMedGoogle Scholar
  105. Russell SM, Tayebi N, Nakajima H, Riedy MC, Roberts JL, Aman MJ, Migone TS, Noguchi M, Markert ML, Buckley RH, O’shea JJ, Leonard WJ (1995) Mutation of Jak3 in a patient with SCID: essential role of Jak3 in lymphoid development. Science 270:797–800PubMedGoogle Scholar
  106. Sadlack B, Kuhn R, Schorle H, Rajewsky K, Muller W, Horak I (1994) Development and proliferation of lymphocytes in mice deficient for both interleukins-2 and-4. Eur J Immunol 24:281–284PubMedGoogle Scholar
  107. Schorle H, Holtschke T, Hunig T, Schimpl A, Horak I (1991) Development and function of T cells in mice rendered interleukin-2 deficient by gene targeting. Nature 352:621–624CrossRefPubMedGoogle Scholar
  108. Sharon M, Klausner RD, Cullen BR, Chizzonite R, Leonard WJ (1986) Novel interleukin-2 receptor subunit detected by cross-linking under high-affinity conditions. Science 234:859–863PubMedGoogle Scholar
  109. Shi YF, Sahai BM, Green DR (1989) Cyclosporin A inhibits activation-induced cell death in T-cell hybridomas and thymocytes. Nature 339:625–626CrossRefPubMedGoogle Scholar
  110. Shurin MR, Tourkova IL, Hackstein H, Shurin GV (2003) Interleukin-15 and 21. In: Thompson AW, Lotze MJ (eds) The cytokine handbook. Academic Press, Amsterdam, pp 431–464Google Scholar
  111. Sporri B, Kovanen PE, Sasaki A, Yoshimura A, Leonard WJ (2001) JAB/SOCS1/SSI-1 is an interleukin-2-induced inhibitor of IL-2 signaling. Blood 97:221–226CrossRefPubMedGoogle Scholar
  112. Suzuki H, Kundig TM, Furlonger C, Wakeham A, Timms E, Matsuyama T, Schmits R, Simard JJ, Ohashi PS, Griesser H, Taniguchi T, Paige CJ, Mak TW (1995) Deregulated T cell activation and autoimmunity in mice lacking interleukin-2 receptor beta. Science 268:1472–1476PubMedGoogle Scholar
  113. Suzuki H, Duncan GS, Takimoto H, Mak TW (1997a) Abnormal development of intestinal intraepithelial lymphocytes and peripheral natural killer cells in mice lacking the IL-2 receptor beta chain. J Exp Med 185:499–505CrossRefPubMedGoogle Scholar
  114. Suzuki H, Hayakawa A, Bouchard D, Nakashima I, Mak TW (1997b) Normal thymic selection, superantigen-induced deletion and Fas-mediated apoptosis of T cells in IL-2 receptor beta chain-deficient mice. Int Immunol 9:1367–1374CrossRefPubMedGoogle Scholar
  115. Suzuki J, Takeshita T, Ohbo K, Asao H, Tada K, Sugamura K (1989) IL-2 receptor subunit, p75: direct demonstration of its IL-2 binding ability by using a novel monoclonal antibody. Int Immunol 1:373–377PubMedGoogle Scholar
  116. Tagaya Y, Bamford RN, DeFilippis AP, Waldmann TA (1996a) IL-15: a pleiotropic cytokine with diverse receptor/signaling pathways whose expression is controlled at multiple levels. Immunity 4:329–336CrossRefPubMedGoogle Scholar
  117. Tagaya Y, Burton JD, Miyamoto Y, Waldmann TA (1996b) Identification of a novel receptor/signal transduction pathway for IL-15/T in mast cells. Embo J 15:4928–4939PubMedGoogle Scholar
  118. Takeshita T, Asao H, Ohtani K, Ishii N, Kumaki S, Tanaka N, Munakata H, Nakamura M, Sugamura K (1992) Cloning of the gamma chain of the human IL-2 receptor. Science 257:379–382PubMedGoogle Scholar
  119. Taniguchi T, Minami Y (1993) The IL-2/IL-2 receptor system: a current overview. Cell 73:5–8CrossRefPubMedGoogle Scholar
  120. Thomis DC, Gurniak CB, Tivol E, Sharpe AH, Berg LJ (1995) Defects in B lymphocyte maturation and T lymphocyte activation in mice lacking Jak3. Science 270:794–797PubMedGoogle Scholar
  121. Tinubu SA, Hakimi J, Kondas JA, Bailon P, Familletti PC, Spence C, Crittenden MD, Parenteau GL, Dirbas FM, Tsudo M, Bacher JD, Kasten-sportes C, Martinucci TL, Goldman CK, Clark RE, Waldmann TA (1994) Humanized antibody directed to the IL-2 receptor beta-chain prolongs primate cardiac allograft survival. J Immunol 153:4330–4338PubMedGoogle Scholar
  122. Tsudo M, Kozak RW, Goldman CK, Waldmann TA (1986) Demonstration of a non-Tac peptide that binds interleukin 2: a potential participant in a multichain interleukin 2 receptor complex. Proc Natl Acad Sci USA 83:9694–9698PubMedGoogle Scholar
  123. Tsudo M, Goldman CK, Bongiovanni KF, Chan WC, Winton EF, Yagita M, Grimm EA, Waldmann TA (1987) The p75 peptide is the receptor for interleukin 2 expressed on large granular lymphocytes and is responsible for the interleukin 2 activation of these cells. Proc Natl Acad Sci USA 84:5394–5398PubMedGoogle Scholar
  124. Tsudo M, Kitamura F, Miyasaka M (1989) Characterization of the interleukin 2 receptor beta chain using three distinct monoclonal antibodies. Proc Natl Acad Sci USA 86:1982–1986PubMedGoogle Scholar
  125. Uchiyama T, Broder S, Waldmann TA (1981) A monoclonal antibody (anti-Tac) reactive with activated and functionally mature human T cells. I. Production of anti-Tac monoclonal antibody and distribution of Tac (+) cells. J Immunol 126:1393–1397PubMedGoogle Scholar
  126. Vámosi G, Bodnar A, Vereb G, Jenei A, Goldman CK, Langowski J, Toth K, Matyus L, Szöllősi J, Waldmann T, Damjanovich S (2004) IL-2 and IL-15 receptor α-subunits are coexpressed in a supramolecular cluster in lipid rafts of T cells. Proc Natl Acad Sci USA 101:11082–11084CrossRefPubMedGoogle Scholar
  127. Villadsen LS, Schuurman J, Beurskens F, Dam TN, Dagnaes-Hansen F, Skov L, Rygaard J, Voorhorst-Ogink MM, Gerritsen AF, van Dijk MA, Parren PW, Baadsgaard O, can de Winkel JG (2003) Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model. J Clin Invest 112:1571–1580CrossRefPubMedGoogle Scholar
  128. Vincenti F, Kirkman R, Light S, Bumgardner G, Pescovitz M, Halloran P, Neylan J, Wilkinson A, Ekberg H, Gaston R, Backman L, Burdick J (1998) Interleukin-2-receptor blockade with daclizumab to prevent acute rejection in renal transplantation. Daclizumab Triple Therapy Study Group. N Engl J Med 338:161–165CrossRefPubMedGoogle Scholar
  129. Waldmann TA (1989a) The multi-subunit interleukin-2 receptor. Annu Rev Biochem 58:875–911CrossRefPubMedGoogle Scholar
  130. Waldmann TA (1989b) Multichain interleukin-2 receptor: a target for immunotherapy in lymphoma. J Natl Cancer Inst 81:914–923PubMedGoogle Scholar
  131. Waldmann TA (1991) The interleukin-2 receptor. J Biol Chem 266:2681–2684PubMedGoogle Scholar
  132. Waldmann TA (1992) Immune receptors: targets for therapy of leukemia/lymphoma, autoimmune diseases and for the prevention of allograft rejection. Annu Rev Immunol 10:675–704PubMedGoogle Scholar
  133. Waldmann TA (1993) The IL-2/IL-2 receptor system: a target for rational immune intervention. Immunol Today 14:264–270CrossRefPubMedGoogle Scholar
  134. Waldmann TA, Tagaya Y (1999) The multifaceted regulation of interleukin-15 expression and the role of this cytokine in NK cell differentiation and host response to intracellular pathogens. Annu Rev Immunol 17:19–49CrossRefPubMedGoogle Scholar
  135. Waldmann TA, White JD, Goldman CK, Top L, Grant A, Bamford R, Roessler E, Horak ID, Zaknoen S, Kasten-Sportes C (1993) The interleukin-2 receptor: a target for monoclonal antibody treatment of human T-cell lymphotrophic virus I-induced adult T-cell leukemia. Blood 82:1701–1712PubMedGoogle Scholar
  136. Waldmann TA, White JD, Carrasquillo JA, Reynolds JC, Paik CH, Gansow OA, Brechbiel MW, Jaffe ES, Fleisher TA, Goldman CK (1995) Radioimmunotherapy of interleukin-2R alpha-expressing adult T-cell leukemia with Yttrium-90-labeled anti-Tac. Blood 86:4063–4075PubMedGoogle Scholar
  137. Waldmann TA, Dubois S, Tagaya Y (2001) Contrasting roles of IL-2 and IL-15 in the life and death of lymphocytes: implications for immunotherapy. Immunity 14:105–110PubMedGoogle Scholar
  138. Wang HM, Smith KA (1987) The interleukin 2 receptor. Functional consequences of its bimolecular structure. J Exp Med 166:1055–1069CrossRefPubMedGoogle Scholar
  139. Willerford DM, Chen J, Ferry JA, Davidson L, Ma A, Alt FW (1995) Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment. Immunity 3:521–530CrossRefPubMedGoogle Scholar
  140. Witthuhn BA, Silvennoinen O, Miura O, Lai KS, Cwik C, Liu ET, Ihle JN (1994) Involvement of the Jak-3 Janus kinase in signalling by interleukins 2 and 4 in lymphoid and myeloid cells. Nature 370:153–157CrossRefPubMedGoogle Scholar
  141. Xanthoudakis S, Viola JP, Shaw KT, Luo C, Wallace JD, Bozza PT, Luk DC, Curran T, Rao A (1996) An enhanced immune response in mice lacking the transcription factor NFAT1. Science 272:892–895PubMedGoogle Scholar
  142. Yoshimura A, Ohkubo T, Kiguchi T, Jenkins NA, Gilbert DJ, Copeland NG, Hara T, Miyajima A (1995) A novel cytokine-inducible gene CIS encodes an SH2-containing protein that binds to tyrosine-phosphorylated interleukin 3 and erythropoietin receptors. Embo J 14:2816–2826PubMedGoogle Scholar
  143. Yu XZ, Levin SD, Madrenas J, Anasetti C (2004) Lck is required for activation-induced T cell death after TCR ligation with partial agonists. J Immunol 172:1437–1443PubMedGoogle Scholar
  144. Zhang X, Sun S, Hwang I, Tough DF, Sprent J (1998) Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity 8:591–599CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2005

Authors and Affiliations

  • Thomas A. Waldmann
  • Sigrid Dubois
  • Jürgen Müller
  • Carolyn Goldman
  • Sándor Damjanovich

There are no affiliations available

Personalised recommendations