1932

Abstract

Cytokines exert a vast array of immunoregulatory actions critical to human biology and disease. However, the desired immunotherapeutic effects of native cytokines are often mitigated by toxicity or lack of efficacy, either of which results from cytokine receptor pleiotropy and/or undesired activation of off-target cells. As our understanding of the structural principles of cytokine–receptor interactions has advanced, mechanism-based manipulation of cytokine signaling through protein engineering has become an increasingly feasible and powerful approach. Modified cytokines, both agonists and antagonists, have been engineered with narrowed target cell specificities, and they have also yielded important mechanistic insights into cytokine biology and signaling. Here we review the theory and practice of cytokine engineering and rationalize the mechanisms of several engineered cytokines in the context of structure. We discuss specific examples of how structure-based cytokine engineering has opened new opportunities for cytokines as drugs, with a focus on the immunotherapeutic cytokines interferon, interleukin-2, and interleukin-4.

Loading

Article metrics loading...

/content/journals/10.1146/annurev-immunol-032713-120211
2015-03-21
2024-12-06
Loading full text...

Full text loading...

/deliver/fulltext/immunol/33/1/annurev-immunol-032713-120211.html?itemId=/content/journals/10.1146/annurev-immunol-032713-120211&mimeType=html&fmt=ahah

Literature Cited

  1. Watowich SS, Hilton DJ, Lodish HF. 1.  1994. Activation and inhibition of erythropoietin receptor function: role of receptor dimerization. Mol. Cell. Biol. 14:3535–49 [Google Scholar]
  2. Wang X, Lupardus P, Laporte SL, Garcia KC. 2.  2009. Structural biology of shared cytokine receptors. Annu. Rev. Immunol. 27:29–60 [Google Scholar]
  3. Stroud RM, Wells JA. 3.  2004. Mechanistic diversity of cytokine receptor signaling across cell membranes. Sci. STKE 2004:re7 [Google Scholar]
  4. Kossiakoff AA, De Vos AM. 4.  1998. Structural basis for cytokine hormone-receptor recognition and receptor activation. Adv. Protein Chem. 52:67–108 [Google Scholar]
  5. Schreiber G, Walter MR. 5.  2010. Cytokine-receptor interactions as drug targets. Curr. Opin. Chem. Biol. 14:511–19 [Google Scholar]
  6. Broughton SE, Hercus TR, Lopez AF, Parker MW. 6.  2012. Cytokine receptor activation at the cell surface. Curr. Opin. Struct. Biol. 22:350–59 [Google Scholar]
  7. Boulanger MJ, Garcia KC. 7.  2004. Shared cytokine signaling receptors: structural insights from the gp130 system. Adv. Protein Chem. 68:107–46 [Google Scholar]
  8. Bazan JF. 8.  1990. Haemopoietic receptors and helical cytokines. Immunol. Today 11:350–54 [Google Scholar]
  9. Bazan JF. 9.  1989. A novel family of growth factor receptors: a common binding domain in the growth hormone, prolactin, erythropoietin and IL-6 receptors, and the p75 IL-2 receptor β-chain. Biochem. Biophys. Res. Commun. 164:788–95 [Google Scholar]
  10. Rochman Y, Spolski R, Leonard WJ. 10.  2009. New insights into the regulation of T cells by γc family cytokines. Nat. Rev. Immunol. 9:480–90 [Google Scholar]
  11. O'Shea JJ, Plenge R. 11.  2012. JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 36:542–50 [Google Scholar]
  12. Ihle JN, Witthuhn BA, Quelle FW, Yamamoto K, Silvennoinen O. 12.  1995. Signaling through the hematopoietic cytokine receptors. Annu. Rev. Immunol. 13:369–98 [Google Scholar]
  13. Levy DE, Darnell JE Jr. 13.  2002. Stats: transcriptional control and biological impact. Nat. Rev. Mol. Cell Biol. 3:651–62 [Google Scholar]
  14. Murray PJ. 14.  2007. The JAK-STAT signaling pathway: input and output integration. J. Immunol. 178:2623–29 [Google Scholar]
  15. Platanias LC. 15.  2005. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol. 5:375–86 [Google Scholar]
  16. van Boxel-Dezaire AH, Rani MR, Stark GR. 16.  2006. Complex modulation of cell type-specific signaling in response to type I interferons. Immunity 25:361–72 [Google Scholar]
  17. Schindler C, Levy DE, Decker T. 17.  2007. JAK-STAT signaling: from interferons to cytokines. J. Biol. Chem. 282:20059–63 [Google Scholar]
  18. Malek TR. 18.  2008. The biology of interleukin-2. Annu. Rev. Immunol. 26:453–79 [Google Scholar]
  19. Heinrich PC, Behrmann I, Haan S, Hermanns HM, Muller-Newen G, Schaper F. 19.  2003. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem. J. 374:1–20 [Google Scholar]
  20. Broughton SE, Dhagat U, Hercus TR, Nero TL, Grimbaldeston MA. 20.  et al. 2012. The GM-CSF/IL-3/IL-5 cytokine receptor family: from ligand recognition to initiation of signaling. Immunol. Rev. 250:277–302 [Google Scholar]
  21. Kallen KJ, Grotzinger J, Rose-John S. 21.  2000. New perspectives on the design of cytokines and growth factors. Trends Biotechnol. 18:455–61 [Google Scholar]
  22. Wells JA, de Vos AM. 22.  1996. Hematopoietic receptor complexes. Annu. Rev. Biochem. 65:609–34 [Google Scholar]
  23. Syed RS, Reid SW, Li C, Cheetham JC, Aoki KH. 23.  et al. 1998. Efficiency of signalling through cytokine receptors depends critically on receptor orientation. Nature 395:511–16 [Google Scholar]
  24. Watowich SS, Wu H, Socolovsky M, Klingmuller U, Constantinescu SN, Lodish HF. 24.  1996. Cytokine receptor signal transduction and the control of hematopoietic cell development. Annu. Rev. Cell Dev. Biol. 12:91–128 [Google Scholar]
  25. Cunningham BC, Ultsch M, De Vos AM, Mulkerrin MG, Clauser KR, Wells JA. 25.  1991. Dimerization of the extracellular domain of the human growth hormone receptor by a single hormone molecule. Science 254:821–25 [Google Scholar]
  26. Constantinescu SN, Keren T, Socolovsky M, Nam H, Henis YI, Lodish HF. 26.  2001. Ligand-independent oligomerization of cell-surface erythropoietin receptor is mediated by the transmembrane domain. PNAS 98:4379–84 [Google Scholar]
  27. Livnah O, Stura EA, Middleton SA, Johnson DL, Jolliffe LK, Wilson IA. 27.  1999. Crystallographic evidence for preformed dimers of erythropoietin receptor before ligand activation. Science 283:987–90 [Google Scholar]
  28. Brooks AJ, Dai W, O'Mara ML, Abankwa D, Chhabra Y. 28.  et al. 2014. Mechanism of activation of protein kinase JAK2 by the growth hormone receptor. Science 344:1249783 [Google Scholar]
  29. Lemmon MA, Schlessinger J. 29.  2010. Cell signaling by receptor tyrosine kinases. Cell 141:1117–34 [Google Scholar]
  30. Ozaki K, Leonard WJ. 30.  2002. Cytokine and cytokine receptor pleiotropy and redundancy. J. Biol. Chem. 277:29355–58 [Google Scholar]
  31. Hercus TR, Dhagat U, Kan WL, Broughton SE, Nero TL. 31.  et al. 2013. Signalling by the βc family of cytokines. Cytokine Growth Factor Rev. 24:189–201 [Google Scholar]
  32. de Vos AM, Ultsch M, Kossiakoff AA. 32.  1992. Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. Science 255:306–12 [Google Scholar]
  33. Pestka S, Krause CD, Walter MR. 33.  2004. Interferons, interferon-like cytokines, and their receptors. Immunol. Rev. 202:8–32 [Google Scholar]
  34. Rickert M, Boulanger MJ, Goriatcheva N, Garcia KC. 34.  2004. Compensatory energetic mechanisms mediating the assembly of signaling complexes between interleukin-2 and its α, β, and γc receptors. J. Mol. Biol. 339:1115–28 [Google Scholar]
  35. Letzelter F, Wang Y, Sebald W. 35.  1998. The interleukin-4 site-2 epitope determining binding of the common receptor gamma chain. Eur. J. Biochem. 257:11–20 [Google Scholar]
  36. LaPorte SL, Juo ZS, Vaclavikova J, Colf LA, Qi X. 36.  et al. 2008. Molecular and structural basis of cytokine receptor pleiotropy in the interleukin-4/13 system. Cell 132:259–72 [Google Scholar]
  37. Ring AM, Lin JX, Feng D, Mitra S, Rickert M. 37.  et al. 2012. Mechanistic and structural insight into the functional dichotomy between IL-2 and IL-15. Nat. Immunol. 13:1187–95 [Google Scholar]
  38. Roisman LC, Jaitin DA, Baker DP, Schreiber G. 38.  2005. Mutational analysis of the IFNAR1 binding site on IFNα2 reveals the architecture of a weak ligand-receptor binding-site. J. Mol. Biol. 353:271–81 [Google Scholar]
  39. Kalie E, Jaitin DA, Podoplelova Y, Piehler J, Schreiber G. 39.  2008. The stability of the ternary interferon-receptor complex rather than the affinity to the individual subunits dictates differential biological activities. J. Biol. Chem. 283:32925–36 [Google Scholar]
  40. Thomas C, Moraga I, Levin D, Krutzik PO, Podoplelova Y. 40.  et al. 2011. Structural linkage between ligand discrimination and receptor activation by type I interferons. Cell 146:621–32 [Google Scholar]
  41. Kruse N, Tony HP, Sebald W. 41.  1992. Conversion of human interleukin-4 into a high affinity antagonist by a single amino acid replacement. EMBO J. 11:3237–44 [Google Scholar]
  42. Kraich M, Klein M, Patino E, Harrer H, Nickel J. 42.  et al. 2006. A modular interface of IL-4 allows for scalable affinity without affecting specificity for the IL-4 receptor. BMC Biol. 4:13 [Google Scholar]
  43. Fuh G, Cunningham BC, Fukunaga R, Nagata S, Goeddel DV, Wells JA. 43.  1992. Rational design of potent antagonists to the human growth hormone receptor. Science 256:1677–80 [Google Scholar]
  44. Lowman HB, Wells JA. 44.  1993. Affinity maturation of human growth hormone by monovalent phage display. J. Mol. Biol. 234:564–78 [Google Scholar]
  45. Boulanger MJ, Chow DC, Brevnova EE, Garcia KC. 45.  2003. Hexameric structure and assembly of the interleukin-6/IL-6 α-receptor/gp130 complex. Science 300:2101–4 [Google Scholar]
  46. Chow D, He X, Snow AL, Rose-John S, Garcia KC. 46.  2001. Structure of an extracellular gp130 cytokine receptor signaling complex. Science 291:2150–55 [Google Scholar]
  47. Bravo J, Heath JK. 47.  2000. Receptor recognition by gp130 cytokines. EMBO J. 19:2399–411 [Google Scholar]
  48. Matadeen R, Hon WC, Heath JK, Jones EY, Fuller S. 48.  2007. The dynamics of signal triggering in a gp130-receptor complex. Structure 15:441–48 [Google Scholar]
  49. Carr PD, Gustin SE, Church AP, Murphy JM, Ford SC. 49.  et al. 2001. Structure of the complete extracellular domain of the common beta subunit of the human GM-CSF, IL-3, and IL-5 receptors reveals a novel dimer configuration. Cell 104:291–300 [Google Scholar]
  50. Tamada T, Honjo E, Maeda Y, Okamoto T, Ishibashi M. 50.  et al. 2006. Homodimeric cross-over structure of the human granulocyte colony-stimulating factor (GCSF) receptor signaling complex. PNAS 103:3135–40 [Google Scholar]
  51. Boulanger MJ, Chow D, Brevnova E, Martick M, Sandford G. 51.  et al. 2004. Molecular mechanisms for viral mimicry of a human cytokine: activation of gp130 by HHV-8 interleukin-6. J. Mol. Biol. 335:641–54 [Google Scholar]
  52. Beyer BM, Ingram R, Ramanathan L, Reichert P, Le HV. 52.  et al. 2008. Crystal structures of the pro-inflammatory cytokine interleukin-23 and its complex with a high-affinity neutralizing antibody. J. Mol. Biol. 382:942–55 [Google Scholar]
  53. Lupardus PJ, Garcia KC. 53.  2008. The structure of interleukin-23 reveals the molecular basis of p40 subunit sharing with interleukin-12. J. Mol. Biol. 382:931–41 [Google Scholar]
  54. Fairlie WD, Uboldi AD, McCoubrie JE, Wang CC, Lee EF. 54.  et al. 2003. Affinity maturation of leukemia inhibitory factor and conversion to potent antagonists of signaling. J. Biol. Chem. 279:2125–34 [Google Scholar]
  55. Hansen G, Hercus TR, McClure BJ, Stomski FC, Dottore M. 55.  et al. 2008. The structure of the GM-CSF receptor complex reveals a distinct mode of cytokine receptor activation. Cell 134:496–507 [Google Scholar]
  56. Patino E, Kotzsch A, Saremba S, Nickel J, Schmitz W. 56.  et al. 2011. Structure analysis of the IL-5 ligand-receptor complex reveals a wrench-like architecture for IL-5Rα. Structure 19:1864–75 [Google Scholar]
  57. Lupardus PJ, Birnbaum ME, Garcia KC. 57.  2010. Molecular basis for shared cytokine recognition revealed in the structure of an unusually high affinity complex between IL-13 and IL-13Rα2. Structure 18:332–42 [Google Scholar]
  58. Chirifu M, Hayashi C, Nakamura T, Toma S, Shuto T. 58.  et al. 2007. Crystal structure of the IL-15-IL-15Rα complex, a cytokine-receptor unit presented in trans. Nat. Immunol. 8:1001–7 [Google Scholar]
  59. Jones BC, Logsdon NJ, Walter MR. 59.  2008. Structure of IL-22 bound to its high-affinity IL-22R1 chain. Structure 16:1333–44 [Google Scholar]
  60. Josephson K, Logsdon NJ, Walter MR. 60.  2001. Crystal structure of the IL-10/IL-10R1 complex reveals a shared receptor binding site. Immunity 15:35–46 [Google Scholar]
  61. Walter MR, Windsor WT, Nagabhushan TL, Lundell DJ, Lunn CA. 61.  et al. 1995. Crystal structure of a complex between interferon-γ and its soluble high-affinity receptor. Nature 376:230–35 [Google Scholar]
  62. Nicola NA, Hilton DJ. 62.  1998. General classes and functions of four-helix bundle cytokines. Adv. Protein Chem. 52:1–65 [Google Scholar]
  63. Domingues H, Cregut D, Sebald W, Oschkinat H, Serrano L. 63.  1999. Rational design of a GCN4-derived mimetic of interleukin-4. Nat. Struct. Biol. 6:652–56 [Google Scholar]
  64. Laporte SL, Forsyth CM, Cunningham BC, Miercke LJ, Akhavan D, Stroud RM. 64.  2005. De novo design of an IL-4 antagonist and its structure at 1.9 Å. PNAS 102:1889–94 [Google Scholar]
  65. Sprang SR, Bazan JF. 65.  1993. Cytokine structural taxonomy and mechanisms of receptor engagement. Curr. Opin. Struct. Biol. 3:815–27 [Google Scholar]
  66. Bazan JF. 66.  1993. Emerging families of cytokines and receptors. Curr. Biol. 3:603–6 [Google Scholar]
  67. Bazan JF. 67.  1990. Structural design and molecular evolution of a cytokine receptor superfamily. PNAS 87:6934–38 [Google Scholar]
  68. Cunningham BC, Henner DJ, Wells JA. 68.  1990. Engineering human prolactin to bind to the human growth hormone receptor. Science 247:1461–65 [Google Scholar]
  69. Cunningham BC, Bass S, Fuh G, Wells JA. 69.  1990. Zinc mediation of the binding of human growth hormone to the human prolactin receptor. Science 250:1709–12 [Google Scholar]
  70. Cunningham BC, Wells JA. 70.  1989. High-resolution epitope mapping of hGH-receptor interactions by alanine-scanning mutagenesis. Science 244:1081–85 [Google Scholar]
  71. Cunningham BC, Jhurani P, Ng P, Wells JA. 71.  1989. Receptor and antibody epitopes in human growth hormone identified by homolog-scanning mutagenesis. Science 243:1330–36 [Google Scholar]
  72. Cunningham BC, Wells JA. 72.  1991. Rational design of receptor-specific variants of human growth hormone. PNAS 88:3407–11 [Google Scholar]
  73. Frisch C, Schreiber G, Johnson CM, Fersht AR. 73.  1997. Thermodynamics of the interaction of barnase and barstar: changes in free energy versus changes in enthalpy on mutation. J. Mol. Biol. 267:696–706 [Google Scholar]
  74. Pal G, Ultsch MH, Clark KP, Currell B, Kossiakoff AA, Sidhu SS. 74.  2005. Intramolecular cooperativity in a protein binding site assessed by combinatorial shotgun scanning mutagenesis. J. Mol. Biol. 347:489–94 [Google Scholar]
  75. Cassell DJ, Choudhri S, Humphrey R, Martell RE, Reynolds T, Shanafelt AB. 75.  2002. Therapeutic enhancement of IL-2 through molecular design. Curr. Pharm. Des. 8:2171–83 [Google Scholar]
  76. Shanafelt AB, Lin Y, Shanafelt MC, Forte CP, Dubois-Stringfellow N. 76.  et al. 2000. A T-cell-selective interleukin 2 mutein exhibits potent antitumor activity and is well tolerated in vivo. Nat. Biotechnol. 18:1197–202 [Google Scholar]
  77. Kang L, Bondensgaard K, Li T, Hartmann R, Hjorth SA. 77.  2010. Rational design of interleukin-21 antagonist through selective elimination of the γC binding epitope. J. Biol. Chem. 285:12223–31 [Google Scholar]
  78. Kallen KJ, Grotzinger J, Lelievre E, Vollmer P, Aasland D. 78.  et al. 1999. Receptor recognition sites of cytokines are organized as exchangeable modules. Transfer of the leukemia inhibitory factor receptor-binding site from ciliary neurotrophic factor to interleukin-6. J. Biol. Chem. 274:11859–67 [Google Scholar]
  79. Brideau-Andersen AD, Huang X, Sun SC, Chen TT, Stark D. 79.  et al. 2007. Directed evolution of gene-shuffled IFN-α molecules with activity profiles tailored for treatment of chronic viral diseases. PNAS 104:8269–74 [Google Scholar]
  80. Rao BM, Girvin AT, Ciardelli T, Lauffenburger DA, Wittrup KD. 80.  2003. Interleukin-2 mutants with enhanced α-receptor subunit binding affinity. Protein Eng. 16:1081–87 [Google Scholar]
  81. Levin AM, Bates DL, Ring AM, Krieg C, Lin JT. 81.  et al. 2012. Exploiting a natural conformational switch to engineer an interleukin-2 ‘superkine.’. Nature 484:529–33 [Google Scholar]
  82. Clackson T, Wells JA. 82.  1995. A hot spot of binding energy in a hormone-receptor interface. Science 267:383–86 [Google Scholar]
  83. Zhang JL, Simeonowa I, Wang Y, Sebald W. 83.  2002. The high-affinity interaction of human IL-4 and the receptor α chain is constituted by two independent binding clusters. J. Mol. Biol. 315:399–407 [Google Scholar]
  84. Junttila IS, Creusot RJ, Moraga I, Bates DL, Wong MT. 84.  et al. 2012. Redirecting cell-type specific cytokine responses with engineered interleukin-4 superkines. Nat. Chem. Biol. 8:990–98 [Google Scholar]
  85. Kalie E, Jaitin DA, Abramovich R, Schreiber G. 85.  2007. An interferon α2 mutant optimized by phage display for IFNAR1 binding confers specifically enhanced antitumor activities. J. Biol. Chem. 282:11602–11 [Google Scholar]
  86. Zurawski SM, Imler JL, Zurawski G. 86.  1990. Partial agonist/antagonist mouse interleukin-2 proteins indicate that a third component of the receptor complex functions in signal transduction. EMBO J. 9:3899–905 [Google Scholar]
  87. Zurawski SM, Vega F Jr, Huyghe B, Zurawski G. 87.  1993. Receptors for interleukin-13 and interleukin-4 are complex and share a novel component that functions in signal transduction. EMBO J. 12:2663–70 [Google Scholar]
  88. Levin D, Schneider WM, Hoffmann HH, Yarden G, Busetto AG. 88.  et al. 2014. Multifaceted activities of type I interferon are revealed by a receptor antagonist. Sci. Signal. 7:ra50 [Google Scholar]
  89. Boulanger MJ, Bankovich AJ, Kortemme T, Baker D, Garcia KC. 89.  2003. Convergent mechanisms for recognition of divergent cytokines by the shared signaling receptor gp130. Mol. Cell 12:577–89 [Google Scholar]
  90. Chao G, Lau WL, Hackel BJ, Sazinsky SL, Lippow SM, Wittrup KD. 90.  2006. Isolating and engineering human antibodies using yeast surface display. Nat. Protoc. 1:755–68 [Google Scholar]
  91. Boder ET, Wittrup KD. 91.  1997. Yeast surface display for screening combinatorial polypeptide libraries. Nat. Biotechnol. 15:553–57 [Google Scholar]
  92. Levin AM, Weiss GA. 92.  2006. Optimizing the affinity and specificity of proteins with molecular display. Mol. Biosyst. 2:49–57 [Google Scholar]
  93. Piehler J, Thomas C, Garcia KC, Schreiber G. 93.  2012. Structural and dynamic determinants of type I interferon receptor assembly and their functional interpretation. Immunol. Rev. 250:317–34 [Google Scholar]
  94. Gonzalez-Navajas JM, Lee J, David M, Raz E. 94.  2012. Immunomodulatory functions of type I interferons. Nat. Rev. Immunol. 12:125–35 [Google Scholar]
  95. Borden EC, Sen GC, Uze G, Silverman RH, Ransohoff RM. 95.  et al. 2007. Interferons at age 50: past, current and future impact on biomedicine. Nat. Rev. Drug Discov. 6:975–90 [Google Scholar]
  96. Wang BX, Rahbar R, Fish EN. 96.  2011. Interferon: current status and future prospects in cancer therapy. J. Interferon Cytokine Res. 31:545–52 [Google Scholar]
  97. Moraga I, Harari D, Schreiber G, Uze G, Pellegrini S. 97.  2009. Receptor density is key to the α2/β interferon differential activities. Mol. Cell. Biol. 29:4778–87 [Google Scholar]
  98. Lavoie TB, Kalie E, Crisafulli-Cabatu S, Abramovich R, DiGioia G. 98.  et al. 2011. Binding and activity of all human α interferon subtypes. Cytokine 56:282–89 [Google Scholar]
  99. Jaks E, Gavutis M, Uze G, Martal J, Piehler J. 99.  2007. Differential receptor subunit affinities of type I interferons govern differential signal activation. J. Mol. Biol. 366:525–39 [Google Scholar]
  100. Subramaniam PS, Khan SA, Pontzer CH, Johnson HM. 100.  1995. Differential recognition of the type I interferon receptor by interferons τ and α is responsible for their disparate cytotoxicities. PNAS 92:12270–74 [Google Scholar]
  101. Jaitin DA, Roisman LC, Jaks E, Gavutis M, Piehler J. 101.  et al. 2006. Inquiring into the differential action of interferons (IFNs): an IFN-α2 mutant with enhanced affinity to IFNAR1 is functionally similar to IFN-β. Mol. Cell. Biol. 26:1888–97 [Google Scholar]
  102. Schiller JH, Willson JK, Bittner G, Wolberg WH, Hawkins MJ, Borden EC. 102.  1986. Antiproliferative effects of interferons on human melanoma cells in the human tumor colony-forming assay. J. Interferon Res. 6:615–25 [Google Scholar]
  103. de Weerd NA, Vivian JP, Nguyen TK, Mangan NE, Gould JA. 103.  et al. 2013. Structural basis of a unique interferon-β signaling axis mediated via the receptor IFNAR1. Nat. Immunol. 14:901–7 [Google Scholar]
  104. Schoggins JW, Wilson SJ, Panis M, Murphy MY, Jones CT. 104.  et al. 2011. A diverse range of gene products are effectors of the type I interferon antiviral response. Nature 472:481–85 [Google Scholar]
  105. Khabar KS, Al-Haj L, Al-Zoghaibi F, Marie M, Dhalla M. 105.  et al. 2004. Expressed gene clusters associated with cellular sensitivity and resistance towards anti-viral and anti-proliferative actions of interferon. J. Mol. Biol. 342:833–46 [Google Scholar]
  106. Bolen CR, Ding S, Robek MD, Kleinstein SH. 106.  2014. Dynamic expression profiling of type I and type III interferon-stimulated hepatocytes reveals a stable hierarchy of gene expression. Hepatology 59:1262–72 [Google Scholar]
  107. Schneider WM, Chevillotte MD, Rice CM. 107.  2014. Interferon-stimulated genes: a complex web of host defenses. Annu. Rev. Immunol. 32:513–45 [Google Scholar]
  108. da Silva AJ, Brickelmaier M, Majeau GR, Lukashin AV, Peyman J. 108.  et al. 2002. Comparison of gene expression patterns induced by treatment of human umbilical vein endothelial cells with IFN-α2b versus IFN-β1a: understanding the functional relationship between distinct type I interferons that act through a common receptor. J. Interferon Cytokine Res. 22:173–88 [Google Scholar]
  109. Moraga I, Spangler J, Mendoza JL, Garcia KC. 109.  2014. Multifarious determinants of cytokine receptor signaling specificity. Adv. Immunol. 121:1–39 [Google Scholar]
  110. Stemmer WP. 110.  1994. DNA shuffling by random fragmentation and reassembly: in vitro recombination for molecular evolution. PNAS 91:10747–51 [Google Scholar]
  111. Stemmer WP. 111.  1994. Rapid evolution of a protein in vitro by DNA shuffling. Nature 370:389–91 [Google Scholar]
  112. Chang CC, Chen TT, Cox BW, Dawes GN, Stemmer WP. 112.  et al. 1999. Evolution of a cytokine using DNA family shuffling. Nat. Biotechnol. 17:793–97 [Google Scholar]
  113. Bekisz J, Baron S, Balinsky C, Morrow A, Zoon KC. 113.  2010. Antiproliferative properties of type I and type II interferon. Pharmaceuticals 3:994–1015 [Google Scholar]
  114. Grimley PM, Fang H, Rui H, Petricoin EF 3rd, Ray S. 114.  et al. 1998. Prolonged STAT1 activation related to the growth arrest of malignant lymphoma cells by interferon-α. Blood 91:3017–27 [Google Scholar]
  115. Silverman RH, Watling D, Balkwill FR, Trowsdale J, Kerr IM. 115.  1982. The ppp(A2′p)nA and protein kinase systems in wild-type and interferon-resistant Daudi cells. Eur. J. Biochem. 126:333–41 [Google Scholar]
  116. Pereira AA, Jacobson IM. 116.  2009. New and experimental therapies for HCV. Nat. Rev. Gastroenterol. Hepatol. 6:403–11 [Google Scholar]
  117. Pan M, Kalie E, Scaglione BJ, Raveche ES, Schreiber G, Langer JA. 117.  2008. Mutation of the IFNAR-1 receptor binding site of human IFN-α2 generates type I IFN competitive antagonists. Biochemistry 47:12018–27 [Google Scholar]
  118. Darnell JE Jr, Kerr IM, Stark GR. 118.  1994. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 264:1415–21 [Google Scholar]
  119. Ivashkiv LB, Donlin LT. 119.  2014. Regulation of type I interferon responses. Nat. Rev. Immunol. 14:36–49 [Google Scholar]
  120. Liao W, Lin JX, Leonard WJ. 120.  2013. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38:13–25 [Google Scholar]
  121. Boyman O, Sprent J. 121.  2012. The role of interleukin-2 during homeostasis and activation of the immune system. Nat. Rev. Immunol. 12:180–90 [Google Scholar]
  122. Klapper JA, Downey SG, Smith FO, Yang JC, Hughes MS. 122.  et al. 2008. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma: a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer 113:293–301 [Google Scholar]
  123. Smith FO, Downey SG, Klapper JA, Yang JC, Sherry RM. 123.  et al. 2008. Treatment of metastatic melanoma using interleukin-2 alone or in conjunction with vaccines. Clin. Cancer Res. 14:5610–18 [Google Scholar]
  124. Pellegrini M, Mak TW, Ohashi PS. 124.  2010. Fighting cancers from within: augmenting tumor immunity with cytokine therapy. Trends Pharmacol. Sci. 31:356–63 [Google Scholar]
  125. Boyman O, Surh CD, Sprent J. 125.  2006. Potential use of IL-2/anti-IL-2 antibody immune complexes for the treatment of cancer and autoimmune disease. Expert Opin. Biol. Ther. 6:1323–31 [Google Scholar]
  126. McDermott DF, Atkins MB. 126.  2004. Application of IL-2 and other cytokines in renal cancer. Expert Opin. Biol. Ther. 4:455–68 [Google Scholar]
  127. Rosenberg SA, Yang JC, White DE, Steinberg SM. 127.  1998. Durability of complete responses in patients with metastatic cancer treated with high-dose interleukin-2: identification of the antigens mediating response. Ann. Surg. 228:307–19 [Google Scholar]
  128. Rosenberg SA. 128.  2012. Raising the bar: the curative potential of human cancer immunotherapy. Sci. Transl. Med. 4:127ps8 [Google Scholar]
  129. Kim HP, Imbert J, Leonard WJ. 129.  2006. Both integrated and differential regulation of components of the IL-2/IL-2 receptor system. Cytokine Growth Factor Rev. 17:349–66 [Google Scholar]
  130. Taniguchi T, Minami Y. 130.  1993. The IL-2/IL-2 receptor system: a current overview. Cell 73:5–8 [Google Scholar]
  131. Liao W, Lin JX, Leonard WJ. 131.  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. 23:598–604 [Google Scholar]
  132. Malek TR, Bayer AL. 132.  2004. Tolerance, not immunity, crucially depends on IL-2. Nat. Rev. Immunol. 4:665–74 [Google Scholar]
  133. Wang X, Rickert M, Garcia KC. 133.  2005. Structure of the quaternary complex of interleukin-2 with its α, β, and γc receptors. Science 310:1159–63 [Google Scholar]
  134. Stauber DJ, Debler EW, Horton PA, Smith KA, Wilson IA. 134.  2006. Crystal structure of the IL-2 signaling complex: paradigm for a heterotrimeric cytokine receptor. PNAS 103:2788–93 [Google Scholar]
  135. Rao BM, Driver I, Lauffenburger DA, Wittrup KD. 135.  2005. High-affinity CD25-binding IL-2 mutants potently stimulate persistent T cell growth. Biochemistry 44:10696–701 [Google Scholar]
  136. Liu DV, Maier LM, Hafler DA, Wittrup KD. 136.  2009. Engineered interleukin-2 antagonists for the inhibition of regulatory T cells. J. Immunother. 32:887–94 [Google Scholar]
  137. Carmenate T, Pacios A, Enamorado M, Moreno E, Garcia-Martinez K. 137.  et al. 2013. Human IL-2 mutein with higher antitumor efficacy than wild type IL-2. J. Immunol. 190:6230–38 [Google Scholar]
  138. Zurawski SM, Zurawski G. 138.  1992. Receptor antagonist and selective agonist derivatives of mouse interleukin-2. EMBO J. 11:3905–10 [Google Scholar]
  139. Margolin K, Atkins MB, Dutcher JP, Ernstoff MS, Smith JW 2nd. 139.  et al. 2007. Phase I trial of BAY 50-4798, an interleukin-2-specific agonist in advanced melanoma and renal cancer. Clin. Cancer Res. 13:3312–19 [Google Scholar]
  140. Davey RT, Pertel PE, Benson A, Cassell DJ, Gazzard BG. 140.  et al. 2008. Safety, tolerability, pharmacokinetics, and efficacy of an interleukin-2 agonist among HIV-infected patients receiving highly active antiretroviral therapy. J. Interferon Cytokine Res. 28:89–100 [Google Scholar]
  141. Matthews L, Chapman S, Ramchandani MS, Lane HC, Davey RT Jr, Sereti I. 141.  2004. BAY 50-4798, a novel, high-affinity receptor-specific recombinant interleukin-2 analog, induces dose-dependent increases in CD25 expression and proliferation among unstimulated, human peripheral blood mononuclear cells in vitro. Clin. Immunol. 113:248–55 [Google Scholar]
  142. Krieg C, Letourneau S, Pantaleo G, Boyman O. 142.  2010. Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells. PNAS 107:11906–11 [Google Scholar]
  143. Gillessen S, Gnad-Vogt US, Gallerani E, Beck J, Sessa C. 143.  et al. 2013. A phase I dose-escalation study of the immunocytokine EMD 521873 (Selectikine) in patients with advanced solid tumours. Eur. J. Cancer 49:35–44 [Google Scholar]
  144. Laurent J, Touvrey C, Gillessen S, Joffraud M, Vicari M. 144.  et al. 2013. T-cell activation by treatment of cancer patients with EMD 521873 (Selectikine), an IL-2/anti-DNA fusion protein. J. Transl. Med. 11:5 [Google Scholar]
  145. Hemar A, Subtil A, Lieb M, Morelon E, Hellio R, Dautry-Varsat A. 145.  1995. Endocytosis of interleukin 2 receptors in human T lymphocytes: distinct intracellular localization and fate of the receptor α, β, and γ chains. J. Cell Biol. 129:55–64 [Google Scholar]
  146. Gesbert F, Sauvonnet N, Dautry-Varsat A. 146.  2004. Clathrin-independent endocytosis and signalling of interleukin 2 receptors IL-2R endocytosis and signalling. Curr. Top. Microbiol. Immunol. 286:119–48 [Google Scholar]
  147. Berndt WG, Chang DZ, Smith KA, Ciardelli TL. 147.  1994. Mutagenic analysis of a receptor contact site on interleukin-2: preparation of an IL-2 analog with increased potency. Biochemistry 33:6571–77 [Google Scholar]
  148. Fallon EM, Liparoto SF, Lee KJ, Ciardelli TL, Lauffenburger DA. 148.  2000. Increased endosomal sorting of ligand to recycling enhances potency of an interleukin-2 analog. J. Biol. Chem. 275:6790–97 [Google Scholar]
  149. Imler JL, Zurawski G. 149.  1992. Receptor binding and internalization of mouse interleukin-2 derivatives that are partial agonists. J. Biol. Chem. 267:13185–90 [Google Scholar]
  150. Chang DZ, Wu Z, Ciardelli TL. 150.  1996. A point mutation in interleukin-2 that alters ligand internalization. J. Biol. Chem. 271:13349–55 [Google Scholar]
  151. Chang DZ, Tasayco ML, Ciardelli TL. 151.  1995. Structural analogs of interleukin-2: a point mutation that facilitates biological response. Mol. Pharmacol. 47:206–11 [Google Scholar]
  152. Braisted AC, Oslob JD, Delano WL, Hyde J, McDowell RS. 152.  et al. 2003. Discovery of a potent small molecule IL-2 inhibitor through fragment assembly. J. Am. Chem. Soc. 125:3714–15 [Google Scholar]
  153. Thanos CD, DeLano WL, Wells JA. 153.  2006. Hot-spot mimicry of a cytokine receptor by a small molecule. PNAS 103:15422–27 [Google Scholar]
  154. Boyman O, Kovar M, Rubinstein MP, Surh CD, Sprent J. 154.  2006. Selective stimulation of T cell subsets with antibody-cytokine immune complexes. Science 311:1924–27 [Google Scholar]
  155. Verdeil G, Marquardt K, Surh CD, Sherman LA. 155.  2008. Adjuvants targeting innate and adaptive immunity synergize to enhance tumor immunotherapy. PNAS 105:16683–88 [Google Scholar]
  156. Jin GH, Hirano T, Murakami M. 156.  2008. Combination treatment with IL-2 and anti-IL-2 mAbs reduces tumor metastasis via NK cell activation. Int. Immunol. 20:783–89 [Google Scholar]
  157. Tomala J, Kovarova J, Kabesova M, Votavova P, Chmelova H. 157.  et al. 2013. Chimera of IL-2 linked to light chain of anti-IL-2 mAb mimics IL-2/anti-IL-2 mAb complexes both structurally and functionally. ACS Chem. Biol. 8:871–76 [Google Scholar]
  158. Waldmann TA. 158.  2006. The biology of interleukin-2 and interleukin-15: implications for cancer therapy and vaccine design. Nat. Rev. Immunol. 6:595–601 [Google Scholar]
  159. Fehniger TA, Caligiuri MA. 159.  2001. Interleukin 15: biology and relevance to human disease. Blood 97:14–32 [Google Scholar]
  160. Castro I, Yu A, Dee MJ, Malek TR. 160.  2011. The basis of distinctive IL-2- and IL-15-dependent signaling: weak CD122-dependent signaling favors CD8+ T central-memory cell survival but not T effector-memory cell development. J. Immunol. 187:5170–82 [Google Scholar]
  161. Fontenot JD, Rasmussen JP, Gavin MA, Rudensky AY. 161.  2005. A function for interleukin 2 in Foxp3-expressing regulatory T cells. Nat. Immunol. 6:1142–51 [Google Scholar]
  162. Maloy KJ, Powrie F. 162.  2005. Fueling regulation: IL-2 keeps CD4+ Treg cells fit. Nat. Immunol. 6:1071–72 [Google Scholar]
  163. Zhang X, Sun S, Hwang I, Tough DF, Sprent J. 163.  1998. Potent and selective stimulation of memory-phenotype CD8+ T cells in vivo by IL-15. Immunity 8:591–99 [Google Scholar]
  164. Schluns KS, Klonowski KD, Lefrancois L. 164.  2004. Transregulation of memory CD8 T-cell proliferation by IL-15Rα+ bone marrow-derived cells. Blood 103:988–94 [Google Scholar]
  165. Becker TC, Wherry EJ, Boone D, Murali-Krishna K, Antia R. 165.  et al. 2002. Interleukin 15 is required for proliferative renewal of virus-specific memory CD8 T cells. J. Exp. Med. 195:1541–48 [Google Scholar]
  166. Pettit DK, Bonnert TP, Eisenman J, Srinivasan S, Paxton R. 166.  et al. 1997. Structure-function studies of interleukin 15 using site-specific mutagenesis, polyethylene glycol conjugation, and homology modeling. J. Biol. Chem. 272:2312–18 [Google Scholar]
  167. Ferrari-Lacraz S, Zheng XX, Kim YS, Li Y, Maslinski W. 167.  et al. 2001. An antagonist IL-15/Fc protein prevents costimulation blockade-resistant rejection. J. Immunol. 167:3478–85 [Google Scholar]
  168. Ferrari-Lacraz S, Zanelli E, Neuberg M, Donskoy E, Kim YS. 168.  et al. 2004. Targeting IL-15 receptor-bearing cells with an antagonist mutant IL-15/Fc protein prevents disease development and progression in murine collagen-induced arthritis. J. Immunol. 173:5818–26 [Google Scholar]
  169. Mortier E, Quemener A, Vusio P, Lorenzen I, Boublik Y. 169.  et al. 2006. Soluble interleukin-15 receptor α (IL-15Rα)-sushi as a selective and potent agonist of IL-15 action through IL-15Rβ/γ: hyperagonist IL-15·IL-15Rα fusion proteins. J. Biol. Chem. 281:1612–19 [Google Scholar]
  170. Zhu X, Marcus WD, Xu W, Lee HI, Han K. 170.  et al. 2009. Novel human interleukin-15 agonists. J. Immunol. 183:3598–607 [Google Scholar]
  171. Han KP, Zhu X, Liu B, Jeng E, Kong L. 171.  et al. 2011. IL-15:IL-15 receptor α superagonist complex: high-level co-expression in recombinant mammalian cells, purification and characterization. Cytokine 56:804–10 [Google Scholar]
  172. Wong HC, Jeng EK, Rhode PR. 172.  2013. The IL-15-based superagonist ALT-803 promotes the antigen-independent conversion of memory CD8 T cells into innate-like effector cells with antitumor activity. Oncoimmunology 2:e26442 [Google Scholar]
  173. Junttila IS, Mizukami K, Dickensheets H, Meier-Schellersheim M, Yamane H. 173.  et al. 2008. Tuning sensitivity to IL-4 and IL-13: differential expression of IL-4Rα, IL-13Rα1, and γc regulates relative cytokine sensitivity. J. Exp. Med. 205:2595–608 [Google Scholar]
  174. Andrews AL, Holloway JW, Holgate ST, Davies DE. 174.  2006. IL-4 receptor α is an important modulator of IL-4 and IL-13 receptor binding: implications for the development of therapeutic targets. J. Immunol. 176:7456–61 [Google Scholar]
  175. Sosman JA, Fisher SG, Kefer C, Fisher RI, Ellis TM. 175.  1994. A phase I trial of continuous infusion interleukin-4 (IL-4) alone and following interleukin-2 (IL-2) in cancer patients. Ann. Oncol. 5:447–52 [Google Scholar]
  176. Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. 176.  2007. Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients: results of two phase 2a studies. Lancet 370:1422–31 [Google Scholar]
  177. Kelly-Welch AE, Hanson EM, Boothby MR, Keegan AD. 177.  2003. Interleukin-4 and interleukin-13 signaling connections maps. Science 300:1527–28 [Google Scholar]
  178. Lutz MB, Schnare M, Menges M, Rossner S, Rollinghoff M. 178.  et al. 2002. Differential functions of IL-4 receptor types I and II for dendritic cell maturation and IL-12 production and their dependency on GM-CSF. J. Immunol. 169:3574–80 [Google Scholar]
  179. Shanafelt AB, Forte CP, Kasper JJ, Sanchez-Pescador L, Wetzel M. 179.  et al. 1998. An immune cell-selective interleukin 4 agonist. PNAS 95:9454–58 [Google Scholar]
  180. Wong MT, Ye JJ, Alonso MN, Landrigan A, Cheung RK. 180.  et al. 2010. Regulation of human Th9 differentiation by type I interferons and IL-21. Immunol. Cell Biol. 88:624–31 [Google Scholar]
  181. Dauer M, Obermaier B, Herten J, Haerle C, Pohl K. 181.  et al. 2003. Mature dendritic cells derived from human monocytes within 48 hours: a novel strategy for dendritic cell differentiation from blood precursors. J. Immunol. 170:4069–76 [Google Scholar]
  182. Wills-Karp M. 182.  2004. Interleukin-13 in asthma pathogenesis. Curr. Allergy Asthma Rep. 4:123–31 [Google Scholar]
  183. Zhu J, Yamane H, Paul WE. 183.  2010. Differentiation of effector CD4 T cell populations. Annu. Rev. Immunol. 28:445–89 [Google Scholar]
  184. Caput D, Laurent P, Kaghad M, Lelias JM, Lefort S. 184.  et al. 1996. Cloning and characterization of a specific interleukin (IL)-13 binding protein structurally related to the IL-5 receptor α chain. J. Biol. Chem. 271:16921–26 [Google Scholar]
  185. Debinski W, Miner R, Leland P, Obiri NI, Puri RK. 185.  1996. Receptor for interleukin (IL) 13 does not interact with IL4 but receptor for IL4 interacts with IL13 on human glioma cells. J. Biol. Chem. 271:22428–33 [Google Scholar]
  186. Candolfi M, Kroeger KM, Xiong W, Liu C, Puntel M. 186.  et al. 2011. Targeted toxins for glioblastoma multiforme: pre-clinical studies and clinical implementation. Anticancer Agents Med. Chem. 11:729–38 [Google Scholar]
  187. Debinski W, Obiri NI, Powers SK, Pastan I, Puri RK. 187.  1995. Human glioma cells overexpress receptors for interleukin 13 and are extremely sensitive to a novel chimeric protein composed of interleukin 13 and pseudomonas exotoxin. Clin. Cancer Res. 1:1253–58 [Google Scholar]
  188. Kunwar S, Prados MD, Chang SM, Berger MS, Lang FF. 188.  et al. 2007. Direct intracerebral delivery of cintredekin besudotox (IL13-PE38QQR) in recurrent malignant glioma: a report by the Cintredekin Besudotox Intraparenchymal Study Group. J. Clin. Oncol. 25:837–44 [Google Scholar]
  189. Liu H, Jacobs BS, Liu J, Prayson RA, Estes ML. 189.  et al. 2000. Interleukin-13 sensitivity and receptor phenotypes of human glial cell lines: non-neoplastic glia and low-grade astrocytoma differ from malignant glioma. Cancer Immunol. Immunother. 49:319–24 [Google Scholar]
  190. Liu H, Prayson RA, Estes ML, Drazba JA, Barnett GH. 190.  et al. 2000. In vivo expression of the interleukin 4 receptor α by astrocytes in epilepsy cerebral cortex. Cytokine 12:1656–61 [Google Scholar]
  191. Debinski W, Gibo DM, Obiri NI, Kealiher A, Puri RK. 191.  1998. Novel anti-brain tumor cytotoxins specific for cancer cells. Nat. Biotechnol. 16:449–53 [Google Scholar]
  192. Candolfi M, Xiong W, Yagiz K, Liu C, Muhammad AK. 192.  et al. 2010. Gene therapy-mediated delivery of targeted cytotoxins for glioma therapeutics. PNAS 107:20021–26 [Google Scholar]
  193. Madhankumar AB, Mintz A, Debinski W. 193.  2004. Interleukin 13 mutants of enhanced avidity toward the glioma-associated receptor, IL13Rα2. Neoplasia 6:15–22 [Google Scholar]
  194. Skiniotis G, Boulanger MJ, Garcia KC, Walz T. 194.  2005. Signaling conformations of the tall cytokine receptor gp130 when in complex with IL-6 and IL-6 receptor. Nat. Struct. Mol. Biol. 12:545–51 [Google Scholar]
  195. Xu Y, Kershaw NJ, Luo CS, Soo P, Pocock MJ. 195.  et al. 2010. Crystal structure of the entire ectodomain of gp130: insights into the molecular assembly of the tall cytokine receptor complexes. J. Biol. Chem. 285:21214–18 [Google Scholar]
  196. Huyton T, Zhang JG, Luo CS, Lou MZ, Hilton DJ. 196.  et al. 2007. An unusual cytokine:Ig-domain interaction revealed in the crystal structure of leukemia inhibitory factor (LIF) in complex with the LIF receptor. PNAS 104:12737–42 [Google Scholar]
  197. Skiniotis G, Lupardus PJ, Martick M, Walz T, Garcia KC. 197.  2008. Structural organization of a full-length gp130/LIF-R cytokine receptor transmembrane complex. Mol. Cell 31:737–48 [Google Scholar]
  198. Walter MR. 198.  2004. Structural analysis of IL-10 and type I interferon family members and their complexes with receptor. Adv. Protein Chem. 68:171–223 [Google Scholar]
/content/journals/10.1146/annurev-immunol-032713-120211
Loading
/content/journals/10.1146/annurev-immunol-032713-120211
Loading

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