CD137 in the Regulation of T Cell Response to Antigen

  • Yuwen Zhu
  • Lieping Chen


CD4+ and CD8+ T cells express high level of CD137 on the cell surface upon activation. A well-documented function of CD137 is its costimulatory effect on both CD4+ and CD8+ T cell growth and differentiation in vitro. In vivo experiments, however, reveal a far more complex effect of CD137 signaling on T cell-mediated immunity. Administration of CD137 agonistic mAb delivers a potent stimulatory signal and leads to CD8 T cell-mediated viral clearance and tumor regression in various models. In sharp contrast, the same agonist mAb is also effective to prevent or even reverse ongoing autoimmune responses, largely mediated through inhibition of CD4+ T cell. In addition to T cells, CD137 is also found on other cells. Therefore, the effect of CD137 should be analyzed in the context of regulator of both innate and adoptive immunity in addition to simply be a T cell costimulator.


Treg Cell CD137 Signal Activation Induce Cell Death Recall Response Cell Anergy 
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. Alderson, M.R., Smith, C.A., Tough, T.W., Davis-Smith, T., Armitage, R.J., Falk, B., Roux, E., Baker, E., Sutherland, G.R., and Din, W.S. (1994). Molecular and biological characterization of human 4-1BB and its ligand. Eur. J. Immunol., 24(9), 2219–2227.PubMedCrossRefGoogle Scholar
  2. Appay, V., Dunbar, P.R., Callan, M., Klenerman, P., Gillespie, G.M., Papagno, L., Ogg, G.S., King, A., Lechner, F., Spina, C.A., et al. (2002). Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat. Med., 8, 379–385.PubMedCrossRefGoogle Scholar
  3. Badovinac, V.P., Porter, B.B., and Harty, J.T. (2002). Programmed contraction of CD8(+) T cells after infection. Nat. Immunol., 3(7), 619–626.PubMedGoogle Scholar
  4. Badovinac, V.P., Porter, B.B., and Harty, J.T. (2004). CD8+ T cell contraction is controlled by early inflammation. Nat. Immunol., 5(8), 809–817.PubMedCrossRefGoogle Scholar
  5. Bansal-Pakala, P., Jember, A.G., and Croft, M. (2001). Signaling through OX40 (CD134) breaks peripheral T-cell tolerance. Nat. Med., 7(8), 907–912.PubMedCrossRefGoogle Scholar
  6. Bansal-Pakala, P., and Croft, M. (2002). Defective T cell priming associated with aging can be rescued by signaling through 4-1BB (CD137). J. Immunol., 169(9), 5005–5009.PubMedGoogle Scholar
  7. Bertram, E.M., Lau, P., and Watts, T.H. (2002). 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., 168(8), 3777–3785.PubMedGoogle Scholar
  8. Bertram, E.M., Dawicki, W., Sedgmen, B., Bramson, J.L., Lynch, D.H., and Watts, T.H. (2004). A switch in costimulation from CD28 to 4-1BB during primary versus secondary CD8 T cell response to influenza in vivo. J. Immunol., 172(2), 981–988.PubMedGoogle Scholar
  9. Blazar, B.R., Kwon, B.S., Panoskaltsis-Mortari, A., Kwak, K.B., Peschon, J.J., and Taylor, P.A. (2001). Ligation of 4-1BB (CDw137) regulates graft-versus-host disease, graft-versus-leukemia, and graft rejection in allogeneic bone marrow transplant recipients. J. Immunol., 166(5), 3174–3183.PubMedGoogle Scholar
  10. Bluestone, J.A., and Abbas, A.K. (2003). Natural versus adaptive regulatory T cells. Nat. Rev. Immunol., 3(3), 253–257.PubMedCrossRefGoogle Scholar
  11. Bukczynski, J., Wen, T., and Watts, T.H. (2003). Costimulation of human CD28− T cells by 4-1BB ligand. Eur. J. Immunol., 33(2), 446–454.PubMedCrossRefGoogle Scholar
  12. Byrne, J.A., Butler, J.L., and Cooper, M.D. (1988). Differential activation requirements for virgin and memory T cells. J. Immunol., 141, 3249–3257.PubMedGoogle Scholar
  13. Callan, M.F., Tan, L., Annels, N., Ogg, G.S., Wilson, J.D., O’Callaghan, C.A., Steven, N., McMichael, A.J., and Rickinson, A.B. (1998). Direct visualization of antigen-specific CD8+ T cells during the primary immune response to Epstein-Barr virus in vivo. J. Exp. Med., 187, 1395–1402.PubMedCrossRefGoogle Scholar
  14. Callan, M.F., Fazou, C., Yang, H., Rostron, T., Poon, K., Hatton, C., and McMichael, A.J. (2000). CD8+ T-cell selection, function, and death in the primary immune response in vivo. J. Clin. Invest., 106(10), 1251–1261.PubMedGoogle Scholar
  15. Cannons, J.L., Lau, P., Ghumman, B., DeBenedette, M.A., Yagita, H., et al. (2001). 4-1BBL induces cell division, sustains survival and enhances effector function of CD4 and CD8 T cells with similar efficacy. J. Immunol., 167, 1313–1324.PubMedGoogle Scholar
  16. Choi, B.K., Bae, J.S., Choi, E.M., Kang, W.J., Sakaguchi, S., Vinay, D.S., and Kwon, B.S. (2004). 4-1BB-dependent inhibition of immunosuppression by activated CD4+CD25+ T cells. J. Leukoc. Biol., 75(5), 785–791.PubMedCrossRefGoogle Scholar
  17. Chu, N.R., DeBenedette, M.A., Stiernholm, B.J., Barber, B.H., and Watts, T.H. (1997). Role of IL-12 and 4-1BB ligand in cytokine production by CD28+ and CD28− T cells. J. Immunol., 158(7), 3081–3089.PubMedGoogle Scholar
  18. Cooper, D., Bansal-Pakala, P., and Croft, M. (2002). 4-1BB (CD137) controls the clonal expansion and survival of CD8 T cells in vivo but does not contribute to the development of cytotoxicity. Eur. J. Immunol., 32(2), 521–529.PubMedCrossRefGoogle Scholar
  19. Croft, M., Bradley, L.M., and Swain, S.L. (1994). Naïve versus memory CD4 T cell response to antigen. Memory cells are less dependent on accessory cell costimulation and can respond to many antigen-presenting cell types including resting B cells. J. Immunol., 152, 2675–2685.PubMedGoogle Scholar
  20. Croft, M. (2003). Co-stimulatory members of the TNFR family: Keys to effective T-cell immunity? Nat. Rev. Immunol., 3(8), 609–620.PubMedCrossRefGoogle Scholar
  21. Dawicki, W., and Watts, T.H. (2004). Expression and function of 4-1BB during CD4 versus CD8 T cell responses in vivo. Eur. J. Immunol., 34(3), 743–751.PubMedCrossRefGoogle Scholar
  22. Dawicki, W., Bertram, E.M., Sharpe, A.H., and Watts, T.H. (2004). 4-1BB and OX40 act independently to facilitate robust CD8 and CD4 recall responses. J. Immunol., 173(10), 5944–5951.PubMedGoogle Scholar
  23. DeBenedette, M.A., Chu, N.R., Pollok, K.E., Hurtado, J., Wade W.F., Kwon, B.S., and Watts, T.H. (1995). Role of 4-1BB ligand in costimulation of T lymphocyte growth and its upregulation on M12 B lymphomas by cAMP. J. Exp. Med., 181(3), 985–992.PubMedCrossRefGoogle Scholar
  24. DeBenedette, M.A., Shahinian, A., Mak, T.W., and Watts, T.H. (1997). Costimulation of CD28− T lymphocytes by 4-1BB ligand. J. Immunol., 158(2), 551–559.PubMedGoogle Scholar
  25. DeBenedette, M.A., Wen, T., Bachmann, M.F., Ohashi, P.S., Barber, B.H., Stocking, K.L., Peschon, J.J., and Watts, T.H. (1999). 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., 163(9), 4833–4841.PubMedGoogle Scholar
  26. Diehl, L., den Boer, A.T., Schoenberger, S.P., van der Voort, E.I., Schumacher, T.N., Melief, C.J., Offringa, R., and Toes, R.E. (1999). CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat. Med., 5(7), 774–779.PubMedCrossRefGoogle Scholar
  27. Diehl, L., van Mierlo, G.J., den Boer, A.T., van der Voort, E., Fransen, M., van Bostelen, L., Krimpenfort, P., Melief, C.J., Mittler, R., Toes, R.E., and Offringa, R. (2002). In vivo triggering through 4-1BB enables Th-independent priming of CTL in the presence of an intact CD28 costimulatory pathway. J. Immunol., 168(8), 3755–3762.PubMedGoogle Scholar
  28. Fallarino, F., Grohmann, U., Hwang, K.W., Orabona, C., Vacca, C., Bianchi, R., Belladonna, M.L., Fioretti, M.C., Alegre, M.L., and Puccetti, P. (2003). Modulation of tryptophan catabolism by regulatory T cells. Nat. Immunol., 4(12), 1206–1212.PubMedCrossRefGoogle Scholar
  29. Foell, J., Strahotin, S., O’Neil, S.P., McCausland, M.M., Suwyn, C., Haber, M., Chander, P.N., Bapat, A.S., Yan, X.J., Chiorazzi, N., Hoffmann, M.K., and Mittler, R.S. (2003). CD137 costimulatory T cell receptor engagement reverses acute disease in lupus-prone NZB × NZW F1 mice. J. Clin. Invest., 111(10), 1505–1518.PubMedCrossRefGoogle Scholar
  30. Fontenot, J.D., Gavin, M.A., and Rudensky, A.Y. (2003). Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol., 4(4), 330–336.PubMedCrossRefGoogle Scholar
  31. Garin, L., Rigal, D., Souillet, G., Bernaud, J., Merieux, Y., and Philippe, N. (1996). Strong increase in the percentage of the CD8bright+ CD28− T-cells and delayed engraftment associated with cyclosporine-induced autologous GVHD. Eur. J. Haematol., 56(3), 119–123.PubMedCrossRefGoogle Scholar
  32. Gavin, M.A., Clarke, S.R., Negrou, E., Gallegos, A., and Rudensky, A. (2002). Homeostasis and anergy of CD4+ CD25+ suppressor T cells in vivo. Nat. Immunol., 3(1), 33–41.PubMedCrossRefGoogle Scholar
  33. Goodwin, R.G., Din, W.S., Davis-Smith, T., Anderson, D.M., Gimpel, S.D., Sato, T.A., Maliszewski, C.R., Brannan, C.I., Copeland, N.G., Jenkins, N.A., et al. (1993). 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., 23(10), 2631–2641.PubMedCrossRefGoogle Scholar
  34. Gramaglia, I., Cooper, D., Miner, K.T., Kwon, B.S., and Croft, M. (2000). Co-stimulation of antigen-specific CD4 T cells by 4-1BB ligand. Eur. J. Immunol., 30, 392–402.PubMedCrossRefGoogle Scholar
  35. Greenwald, R.J., Boussiotis, V.A., Lorsbach, R.B., Abbas, A.K., and Sharpe, A.H. (2001). CTLA-4 regulates induction of anergy in vivo. Immunity, 14(2), 145–155.PubMedCrossRefGoogle Scholar
  36. Hori, S., Nomura, T., and Sakaguchi, S. (2003). Control of regulatory T cell development by the transcription factor Foxp3. Science, 299(5609), 1057–1061.PubMedCrossRefGoogle Scholar
  37. Hurtado, J.C., Kim, S.H., Pollok, K.E., Lee, Z.H., and Kwon, B.S. (1995). Potential role of 4-1BB in T cell activation. Comparison with the costimulatory molecule CD28. J. Immunol., 155(7), 3360–3367.PubMedGoogle Scholar
  38. Ito, F., Li, Q., Shreiner, A.B., Okuyama, R., Jure-Kunkel, M.N., Teitz-Tennenbaum, S., and Chang, A.E. (2004). Anti-CD137 monoclonal antibody administration augments the antitumor efficacy of dendritic cell-based vaccines. Cancer Res., 64(22), 8411–8419.PubMedCrossRefGoogle Scholar
  39. Khattri, R., Cox, T., Yasayko, S.A., and Ramsdell, F. (2003). An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol., 4(4), 337–342.PubMedCrossRefGoogle Scholar
  40. Kim, Y.J., Brutkiewicz, R.R., and Broxmeyer, H.E. (2002). Role of 4-1BB (CD137) in the functional activation of cord blood CD28(−) CD8(+) T cells. Blood, 100(9), 3253–3260.PubMedCrossRefGoogle Scholar
  41. Kim, J., Choi, S.P., La, S., Seo, J.S., Kim, K.K., Nam, S.H., and Kwon, B. (2003). Constitutive expression of 4-1BB on T cells enhances CD4+ T cell responses. Exp. Mol. Med., 35(6), 509–517.PubMedGoogle Scholar
  42. Laderach, D., Movassagh, M., Johnson, A., Mittler, R.S., and Galy, A. (2002). 4-1BB co-stimulation enhances human CD8(+) T cell priming by augmenting the proliferation and survival of effector CD8(+) T cells. Int. Immunol., 14(10), 1155–1167.PubMedCrossRefGoogle Scholar
  43. Lee, H.W., Park, S.J., Choi, B.K., Kim, H.H., Nam, K.O., and Kwon, B.S. (2002). 4-1BB promotes the survival of CD8+ T lymphocytes by increasing expression of Bcl-xL and Bfl-1. J. Immunol., 169, 4882–4888.PubMedGoogle Scholar
  44. Lee, H.W., Nam, K.O., Seo, S.K., Kim, Y.H., Kang, H., and Kwon, B.S. (2003). 4-1BB cross-linking enhances the survival and cell cycle progression of CD4 T lymphocytes. Cell. Immunol., 223(2), 143–150.PubMedCrossRefGoogle Scholar
  45. Lee, S.W., Vella, A.T., Kwon, B.S., and Croft, M. (2005). Enhanced CD4 T cell responsiveness in the absence of 4-1BB. J. Immunol., 174(11), 6803–6808.PubMedGoogle Scholar
  46. London, C.A., Lodge, M.P., and Abbas, A.K. (2000). Functional responses and costimulator dependence of memory CD4+ T cells. J. Immunol., 164, 265–272.PubMedGoogle Scholar
  47. Maus, M.V., Thomas, A.K., Leonard, D.G., Allman, D., Addya, K., Schlienger, K., Riley, J.L., and June, C.H. (2002). Ex vivo expansion of polyclonal and antigen-specific cytotoxic T lymphocytes by artificial APCs expressing ligands for the T-cell receptor, CD28 and 4-1BB. Nat. Biotechnol., 20(2), 143–148.PubMedCrossRefGoogle Scholar
  48. McHugh, R.S., Whitters, M.J., Piccirillo, C.A., Young, D.A., Shevach, E.M., Collins, M., and Byrne. M.C. (2002). CD4+ CD25+ immunoregulatory T cells: Gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity, 16, 311–323.PubMedCrossRefGoogle Scholar
  49. Melero, I., Shuford, W.W., Newby, S.A., Aruffo, A., Ledbetter, J.A., Hellstrom, K.E., Mittler, R.S., and Chen, L. (1997). Monoclonal antibodies against the 4-1BB T-cell activation molecule eradicate established tumors. Nat. Med., 3(6), 682–685.PubMedCrossRefGoogle Scholar
  50. Morris, G.P., Chen, L., and Kong, Y.C. (2003). CD137 signaling interferes with activation and function of CD4+CD25+ regulatory T cells in induced tolerance to experimental autoimmune thyroiditis. Cell. Immunol., 226(1), 20–29.PubMedCrossRefGoogle Scholar
  51. Perez, V.L., Van Parijs, L., Biuckians, A., Zheng, X.X., Strom, T.B., and Abbas, A.K. (1997). Induction of peripheral T cell tolerance in vivo requires CTLA-4 engagement. Immunity., 6(4), 411–417.PubMedCrossRefGoogle Scholar
  52. Pollok, K.E., Kim, Y.J., Zhou, Z., Hurtado, J., Kim, K.K., Pickard, R.T., and Kwon, B.S. (1993). Inducible T cell antigen 4-1BB. Analysis of expression and function. J. Immunol., 150(3), 771–781.PubMedGoogle Scholar
  53. Pollok, K.E., Kim, S.H., and Kwon, B.S. (1995). Regulation of 4-1BB expression by cell-cell interactions and the cytokines, interleukin-2 and interleukin-4. Eur. J. Immunol., 25(2), 488–494.PubMedCrossRefGoogle Scholar
  54. Sakaguchi, S. (2004). Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu. Rev. Immunol., 22, 531–562.PubMedCrossRefGoogle Scholar
  55. Salek-Ardakani, S., Song, J., Halteman, B.S., Jember, A.G., Akiba, H., Yagita, H., and Croft, M. (2003). OX40 (CD134) controls memory T helper 2 cells that drive lung inflammation. J. Exp. Med., 198(2), 315–324.PubMedCrossRefGoogle Scholar
  56. Schwartz, R.H. (2003). T cell anergy. Annu. Rev. Immunol., 21, 305–334.PubMedCrossRefGoogle Scholar
  57. Seo, S.K., Choi, J.H., Kim, Y.H., Kang, W.J., Park, H.Y., Suh, J.H., Choi, B.K., Vinay, D.S., and Kwon, B.S. (2004). 4-1BB-mediated immunotherapy of rheumatoid arthritis. Nat. Med., 10(10), 1088–1094.PubMedCrossRefGoogle Scholar
  58. Shuford, W.W., Klussman, K., Tritchler, D.D., Loo, D.T., Chalupny, J., Siadak, A.W., Brown, T.J., Emswiler, J., Raecho, H., Larsen, C.P., Pearson, T.C., Ledbetter, J.A., Aruffo, A., and Mittler, R.S. (1997). 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., 186(1), 47–55.PubMedCrossRefGoogle Scholar
  59. Starck, L., Scholz, C., Dorken, B., and Daniel, P.T. (2005). 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., 35(4), 1257–1266.PubMedCrossRefGoogle Scholar
  60. Sun, Y., Lin, X., Chen, H.M., Wu, Q., Subudhi, S.K., Chen, L., and Fu, Y.X. (2002a). Administration of agonistic anti-4-1BB monoclonal antibody leads to the amelioration of experimental autoimmune encephalomyelitis. J. Immunol., 168(3), 1457–1465.Google Scholar
  61. Sun, Y., Chen, H.M., Subudhi, S.K., Chen, J., Koka, R., Chen, L., and Fu, Y.X. (2002b). Costimulatory molecule-targeted antibody therapy of a spontaneous autoimmune disease. Nat. Med., 8(12), 1405–1413.CrossRefGoogle Scholar
  62. Takahashi, C., Mittler, R.S., and Vella, A.T. (1999). Cutting edge: 4-1BB is a bona fide CD8 T cell survival signal. J. Immunol., 162(9), 5037–5040.PubMedGoogle Scholar
  63. Tan, J.T., Whitmire, J.K., Ahmed, R., Pearson, T.C., and Larsen, C.P. (1999). 4-1BB ligand, a member of the TNF family, is important for the generation of antiviral CD8 T cell responses. J. Immunol., 163(9), 4859–4868.PubMedGoogle Scholar
  64. Tan, J.T., Whitmire, J.K., Murali-Krishna, K., Ahmed, R., Altman, J.D., Mittler, R.S., Sette, A., Pearson, T.C., and Larsen, C.P. (2000). 4-1BB costimulation is required for protective anti-viral immunity after peptide vaccination. J. Immunol., 164(5), 2320–2325.PubMedGoogle Scholar
  65. Taraban, V.Y., Rowley, T.F., O’Brien, L., Chan, H.T., Haswell, L.E., Green, M.H., Tutt, A.L., Glennie, M.J., and Al-Shamkhani, A. (2002). Expression and costimulatory effects of the TNF receptor superfamily members CD134 (OX40) and CD137 (4-1BB), and their role in the generation of anti-tumor immune responses. Eur. J. Immunol., 32, 3617–3627.PubMedCrossRefGoogle Scholar
  66. Wen, T., Bukczynski, J., and Watts, T.H. (2002). 4-1BB ligand-mediated costimulation of human T cells induces CD4 and CD8 T cell expansion, cytokine production, and the development of cytolytic effector function. J. Immunol., 168(10), 4897–4906.PubMedGoogle Scholar
  67. Werwitzke, S., Drescher, B., Schmidt, R.E., and Witte, T. (2000). CD8+ T cell populations in common variable immunodeficiency. Immunobiology., 202(2), 168–171.PubMedGoogle Scholar
  68. Wilcox, R.A., Tamada, K., Flies, D.B., Zhu, G., Chapoval, A.I., Blazar, B.R., Kast, W.M., and Chen, L. (2004). Ligation of CD137 receptor prevents and reverses established anergy of CD8+ cytolytic T lymphocytes in vivo. Blood., 103(1), 177–184.PubMedCrossRefGoogle Scholar
  69. Zheng, G., Wang, B., and Chen, A. (2004). The 4-1BB costimulation augments the proliferation of CD4+CD25+ regulatory T cells. J. Immunol., 173(4), 2428–2434.PubMedGoogle Scholar

Copyright information

© Springer 2006

Authors and Affiliations

  • Yuwen Zhu
    • 1
  • Lieping Chen
    • 1
  1. 1.Department of Dermatology and OncologyJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations