4-1BB as a Therapeutic Target for Human Disease

  • Seung-Woo Lee
  • Michael Croft
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 647)


4-1BB (CD137) is being thought of as an attractive target for immunotherapy of many human immune diseases based on encouraging results with 4-1BB agonistic antibody treatment in mouse models of cancer, autoimmune disease, asthma and additionally as a means to improve vaccination. In this review, we will summarize the results of basic research on 4-1BB and 4-1BB immunotherapy of disease and provide some potential mechanistic insights into the many stimulatory and regulatory functions of 4-1BB.


Experimental Autoimmune Encephalomyelitis Treg Cell Allergic Conjunctivitis Agonistic Antibody Tumor Necrosis Factor Superfamily 
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. 1.
    Kwon BS, Weissman SM. cDNA sequences of two inducible T-cell genes. Proc Natl Acad Sci USA 1989; 86:1963.PubMedCrossRefGoogle Scholar
  2. 2.
    Schwarz H, Blanco FJ, von Kempis J et al. ILA, a member of the human nerve growth factor/tumor necrosis factor receptor family, regulates T-lymphocyte proliferation and survival. Blood 1996; 87:2839–2845.PubMedGoogle Scholar
  3. 3.
    Watts TH. TNF/TNFR family members in costimulation of T-cell responses. Annu Rev Immunol 2005; 23:23.PubMedCrossRefGoogle Scholar
  4. 4.
    Croft M. Costimulatory members of the TNFR family: keys to effective T-cell immunity? Nat Rev Immunol 2003; 3:609.PubMedCrossRefGoogle Scholar
  5. 5.
    Goodwin RG, Din WS, Davis-Smith T et al. Molecular cloning of a ligand for the inducible T-cell gene 4-1BB: a member of an emerging family of cytokines with homology to tumor necrosis factor. Eur J Immunol 1993; 23:2631.PubMedCrossRefGoogle Scholar
  6. 6.
    Futagawa T, Akiba H, Kodama T et al. Expression and function of 4-1BB and 4-1BB ligand on murine dendritic cells. Int Immunol 2002; 14:275.PubMedCrossRefGoogle Scholar
  7. 7.
    Schwarz H. Biological activities of reverse signal transduction through CD137 ligand. J Leukoc Biol 2004; 77:281.PubMedCrossRefGoogle Scholar
  8. 8.
    Gramaglia I, Cooper D, Miner KT et al. Costimulation of antigen-specific CD4 T-cells by 4-1BB ligand. Eur J Immunol 2000; 30:392.PubMedCrossRefGoogle Scholar
  9. 9.
    Cannons JL, Lau P, Ghumman B et al. 4-1BB ligand induces cell division, sustains survival and enhances effector function of CD4 and CD8 T-cells with similar efficacy. J Immunol 2001; 167:1313.PubMedGoogle Scholar
  10. 10.
    Shuford WW, Klussman K, Tritchler DD et al. 4-1BB costimulatory signals preferentially induce CD8+ T-cell proliferation and lead to the amplification in vivo of cytotoxic T-cell responses. J Exp Med 1997; 186:47.PubMedCrossRefGoogle Scholar
  11. 11.
    Bukczynski J, Wen T, Wang C et al. Enhancement of HIV-specific CD8 T-cell responses by dual costimulation with CD80 and CD137L. J Immunol 2005; 175:6378.PubMedGoogle Scholar
  12. 12.
    Arch RH, Thompson CB. 4-1BB and Ox40 are members of a tumor necrosis factor (TNF)-nerve growth factor receptor subfamily that bind TNF receptor-associated factors and activate nuclear factor kappaB. Mol Cell Biol 1998; 18:558.PubMedGoogle Scholar
  13. 13.
    Jang IK, Lee ZH, Kim YJ et al. Human 4-1BB (CD137) signals are mediated by TRAF2 and activate nuclear factor-kappa B. Biochem Biophys Res Commun 1998; 242:613.PubMedCrossRefGoogle Scholar
  14. 14.
    Ma BY, Mikolajczak SA, Danesh A et al. The expression and the regulatory role of OX40 and 4-1BB heterodimer in activated human T-cells. Blood 2005; 106:2002.PubMedCrossRefGoogle Scholar
  15. 15.
    Starck L, Scholz C, Dorken B et al. Costimulation by CD137/4-1BB inhibits T-cell apoptosis and induces Bcl-xL and c-FLIP(short) via phosphatidylinositol 3-kinase and AKT/protein kinase B. Eur J Immunol 2005; 35:1257.PubMedCrossRefGoogle Scholar
  16. 16.
    Lee HW, Park SJ, Choi BK et al. 4-1BB promotes the survival of CD8+ T-lymphocytes by increasing expression of Bcl-xL and Bfl-1. J Immunol 2002; 169:4882.PubMedGoogle Scholar
  17. 17.
    Kwon BS, Hurtado JC, Lee ZH et al. Immune responses in 4-1BB (CD137)-deficient mice. J Immunol 2002; 168:5483.PubMedGoogle Scholar
  18. 18.
    DeBenedette MA, Wen T, Bachmann MF et al. Analysis of 4-1BB ligand (4-1BBL)-deficient mice and of mice lacking both 4-1BBL and CD28 reveals a role for 4-1BBL in skin allograft rejection and in the cytotoxic T-cell response to influenza virus. J Immunol 1999; 163:4833.PubMedGoogle Scholar
  19. 19.
    Shedlock DJ, Whitmire JK, Tan J et al. Role of CD4 T-cell help and costimulation in CD8 T-cell responses during Listeria monocytogenes infection. J Immunol 2003; 170:2053.PubMedGoogle Scholar
  20. 20.
    Tan JT, Whitmire JK, Ahmed R et al. 4-1BB ligand, a member of the TNF family, is important for the generation of antiviral CD8 T-cell responses. J Immunol 1999; 163:4859.PubMedGoogle Scholar
  21. 21.
    Bertram EM, Lau P, Watts TH. Temporal segregation of 4-1BB versus CD28-mediated costimulation: 4-1BB ligand influences T-cell numbers late in the primary response and regulates the size of the T-cell memory response following influenza infection. J Immunol 2002; 168:3777.PubMedGoogle Scholar
  22. 22.
    Bertram EM, Dawicki W, Sedgmen B et al. A switch in costimulation from CD28 to 4-1BB during primary versus secondary CD8 T-cell response to influenza in vivo. J Immunol 2004; 172:981.PubMedGoogle Scholar
  23. 23.
    Dawicki W, Bertram EM, Sharpe AH et al. 4-1BB and OX40 act independently to facilitate robust CD8 and CD4 recall responses. J Immunol 2004; 173:5944.PubMedGoogle Scholar
  24. 24.
    Lee SW, Vella AT, Kwon BS et al. Enhanced CD4 T-cell responsiveness in the absence of 4-1BB. J Immunol 2005; 174:6803.PubMedGoogle Scholar
  25. 25.
    Lee SW, Park Y, Song A et al. Functional dichotomy between OX40 and 4-1BB in modulating effector CD8 T-cell responses. J Immunol 2006; 177:4464.PubMedGoogle Scholar
  26. 26.
    Zheng G, Wang B, Chen A. The 4-1BB costimulation augments the proliferation of CD4+CD25+ regulatory T-cells. J Immunol 2004; 173:2428.PubMedGoogle Scholar
  27. 27.
    Choi BK, Bae JS, Choi EM et al. 4-1BB-dependent inhibition of immunosuppression by activated CD4+CD25+ T-cells. J Leukoc Biol 2004; 75:785.PubMedCrossRefGoogle Scholar
  28. 28.
    Irie J, Wu Y, Kachapati K et al. Modulating protective and pathogenic CD4+ subsets via CD137 in type 1 diabetes. Diabetes 2007; 56:186.PubMedCrossRefGoogle Scholar
  29. 29.
    Melero I, Johnston JV, Shufford WW et al. NK1.1 cells express 4-1BB (CDw137) costimulatory molecule and are required for tumor immunity elicited by anti-4-1BB monoclonal antibodies. Cell Immunol 1998; 190:167.PubMedCrossRefGoogle Scholar
  30. 30.
    Wilcox RA, Tamada K, Strome SE et al. Signaling through NK-cell-associated CD137 promotes both helper function for CD8+ cytolytic T-cells and responsiveness to IL-2 but not cytolytic activity. J Immunol 2002; 169:4230.PubMedGoogle Scholar
  31. 31.
    Lindstedt M, Johansson-Lindbom B, Borrebaeck CA. Expression of CD137 (4-1BB) on human follicular dendritic cells. Scand J Immunol 2003; 57:305.PubMedCrossRefGoogle Scholar
  32. 32.
    Wilcox RA, Chapoval AI, Gorski KS et al. Cutting edge: Expression of functional CD137 receptor by dendritic cells. J Immunol 2002; 168:4262.PubMedGoogle Scholar
  33. 33.
    Lee SC, Ju SA, Pack HN et al. 4-1BB (CD137) is required for rapid clearance of Listeria monocytogenes infection. Infect Immun 2005; 73:5144.PubMedCrossRefGoogle Scholar
  34. 34.
    Nishimoto H, Lee SW, Hong H et al. Costimulation of mast cells by 4-1BB, a member of the tumor necrosis factor receptor superfamily, with the high-affinity IgE receptor. Blood 2005; 106:4241.PubMedCrossRefGoogle Scholar
  35. 35.
    Kim YJ, Li G, Broxmeyer HE. 4-1BB ligand stimulation enhances myeloid dendritic cell maturation from human umbilical cord blood CD34+ progenitor cells. J Hemathother Stem Cell Res 2002; 11:895.CrossRefGoogle Scholar
  36. 36.
    Melero I, Shuford WW, Newby SA et al. Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat Med 1997; 3:682.PubMedCrossRefGoogle Scholar
  37. 37.
    Melero I, Bach N, Hellstrom KE et al. Amplification of tumor immunity by gene transfer of the costimulatory 4-1BB ligand: synergy with the CD28 costimulatory pathway. Eur J Immunol 1998; 28:1116.PubMedCrossRefGoogle Scholar
  38. 38.
    Guinn BA, DeBenedette MA, Watts TH et al. 4-1BBL cooperates with B7-1 and B7-2 in converting a B-cell lymphoma cell line into a long-lasting antitumor vaccine. J Immunol 1999; 162:5003.PubMedGoogle Scholar
  39. 39.
    Wilcox RA, Flies DB, Zhu G et al. Provision of antigen and CD137 signaling breaks immunological ignorance, promoting regression of poorly immunogenic tumors. J Clin Invest 2002; 109:651.PubMedGoogle Scholar
  40. 40.
    Bansal-Pakala P, Croft M. Defective T-cell priming associated with aging can be rescued by signaling through 4-1BB (CD137). J Immunol 2002; 169:5005.PubMedGoogle Scholar
  41. 41.
    Ye Z, Hellstrom I, Hayden-Ledbetter M et al. Gene therapy for cancer using single-chain Fv fragments specific for 4-1BB. Nat Med 2002; 8:343.PubMedCrossRefGoogle Scholar
  42. 42.
    Ito F, Li Q, Shreiner AB et al. Anti-CD137 monoclonal antibody administration augments the antitumor efficacy of dendritic cell-based vaccines. Cancer Res 2004; 64:8411.PubMedCrossRefGoogle Scholar
  43. 43.
    Pan PY, Gu P, Li Q et al. Regulation of dendritic cell function by NK-cells: mechanisms underlying the synergism in the combination therapy of IL-12 and 4-1BB activation. J Immunol 2004; 172:4779.PubMedGoogle Scholar
  44. 44.
    Xu DP, Sauter BV, Huang TG et al. The systemic administration of Ig-4-1BB ligand in combination with IL-12 gene transfer eradicates hepatic colon carcinoma. Gene Ther 2005; 12:1526.PubMedCrossRefGoogle Scholar
  45. 45.
    Halstead ES, Mueller YM, Altman JD et al. In vivo stimulation of CD137 broadens primary antiviral CD8+ T-cell responses. Nat Immunol 2002; 3:536.PubMedCrossRefGoogle Scholar
  46. 46.
    Munks MW, Mourich DV, Mittler RS et al. 4-1BB and OX40 stimulation enhance CD8 and CD4 T-cell responses to a DNA prime, poxvirus boost vaccine. Immunology 2004; 112:559.PubMedCrossRefGoogle Scholar
  47. 47.
    Arribillaga L, Sarobe P, Arina A et al. Enhancement of CD4 and CD8 immunity by anti-CD137 (4-1BB) monoclonal antibodies during hepatitis C vaccination with recombinant adenovirus. Vaccine 2005; 23:3493.PubMedCrossRefGoogle Scholar
  48. 48.
    Harrison JM, Bertram EM, Boyle DB et al. 4-1BBL coexpression enhances HIV-specific CD8 T-cell memory in a poxvirus prime-boost vaccine. Vaccine 2006; 24:6867.PubMedCrossRefGoogle Scholar
  49. 49.
    Seo SK, Choi JH, Kim YH et al. 4-1BB-mediated immunotherapy of rheumatoid arthritis. Nat Med 2004; 10:1088.PubMedCrossRefGoogle Scholar
  50. 50.
    Fukushima A, Yamaguchi T, Ishida W et al. Engagement of 4-1BB inhibits the development of experimental allergic conjunctivitis in mice. J Immunol 2005; 175:4897.PubMedGoogle Scholar
  51. 51.
    Sun Y, Lin X, Chen HM et al. Administration of agonistic anti-4-1BB monoclonal antibody leads to the amelioration of experimental autoimmune encephalomyelitis. J Immunol 2002; 68:1457.Google Scholar
  52. 52.
    Sun Y, Chen HM, Subudhi SK et al. Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease. Nat Med 2002; 8:1405.PubMedCrossRefGoogle Scholar
  53. 53.
    Foell J, Strahotin S, O’Neil SP et al. CD137 costimulatory T-cell receptor engagement reverses acute disease in lupus-prone NZB x NZW F1 mice. J Clin Invest 2003; 111:1505.PubMedGoogle Scholar
  54. 54.
    Sun Y, Blink SE, Chen JH et al. Regulation of follicular dendritic cell networks by activated T-cells: the role of CD137 signaling. J Immunol 2005; 175:884.PubMedGoogle Scholar
  55. 55.
    Mellor AL, Munn DH. IDO expression by dendritic cells:to lerance and tryptophan catabolism. Nat Rev Immunol 2004; 4:762.PubMedCrossRefGoogle Scholar
  56. 56.
    Cannons JL, Chamberlain G, Howson J et al. Genetic and functional association of the immune signaling molecule 4-1BB (CD137/TNFRSF9) with type 1 diabetes. J Autoimmun 2005; 25:13.PubMedCrossRefGoogle Scholar
  57. 57.
    Polte T, Foell J, Werner C et al. CD137-mediated immunotherapy for allergic asthma. J Clin Invest 2006; 116:1025.PubMedCrossRefGoogle Scholar
  58. 58.
    Sun Y, Blink SE, Liu W et al. Inhibition of Th2-mediated allergic airway inflammatory disease by CD137 costimulation. J Immunol 2006; 177:814.PubMedGoogle Scholar
  59. 59.
    Kim J, Choi WS, La S et al. Stimulation with 4-1BB (CD137) inhibits chronic graft-versus-host disease by inducing activation-induced cell death of donor CD4+ T-cells. Blood 2005; 105:2206.PubMedCrossRefGoogle Scholar
  60. 60.
    Myers L, Croft M, Kwon BS et al. Peptide-specific CD8 T regulatory cells use IFN-β to elaborate TGF-γ-based suppression. J Immunol 2005; 174:7625.PubMedGoogle Scholar
  61. 61.
    Lee J, Lee EN, Kim EY et al. Administration of agonistic anti-4-1BB monoclonal antibody leads to the amelioration of inflammatory bowel disease. Immunol Lett 2005; 101:210.PubMedCrossRefGoogle Scholar
  62. 62.
    Miller RE, Jones J, Le T et al. 4-1BB-specific monoclonal antibody promotes the generation of tumor-specific immune responses by direct activation of CD8 T-cells in a CD40-dependent manner. J Immunol 2002; 169:1792.PubMedGoogle Scholar
  63. 63.
    Vinay DS, Kim JD, Kwon BS. Amelioration of mercury-induced autoimmunity by 4-1BB. J Immunol 2006; 177:5708.PubMedGoogle Scholar
  64. 64.
    Niu L, Strahotin S, Hewes B et al. Cytokine-mediated disruption of lymphocyte trafficking, hemopoiesis, and induction of lymphopenia, anemia, and thrombocytopenia in anti-CD137-treated mice. J Immunol 2007; 178:4194.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2009

Authors and Affiliations

  • Seung-Woo Lee
    • 1
  • Michael Croft
    • 1
  1. 1.Molecular ImmunologyLa Jolla Institute for Allergy and ImmunologyLa JollaUSA

Personalised recommendations