Skip to main content
Log in

The role of CD40-CD154 interaction in cell immunoregulation

  • Review
  • Published:
Journal of Biomedical Science

Abstract

CD40, a member of the nerve growth factor/tumor necrosis factor receptor superfamily, and its ligand, CD154, play essential roles in cell immune responses. The results of many studies have indicated that CD40-CD154 interaction can upregulate costimulatory molecules, activate antigen-presenting cells (APCs), influence T-cell priming and T-cell-mediated effector functions as well as participate in the pathogenic processing of chronic inflammatory diseases, such as autoimmune diabetes, graft rejection, atherosclerosis, and cancer. Ligation of CD40 on cancer cells was also found to produce a direct growth-inhibitory effect through cell cycle blockage and/or apoptosis with no overt side effects on normal cells and treatment with CD154 can heighten tumor rejection immune response as well. However, systemic treatment with CD154 has some potential risks. Therefore, searching for efficient and safe strategies of CD154-based cancer therapy has been a hot topic in human cancer research. This review focuses on the latest discovered functions of CD40-CD154 interaction in cell immune responses and on the new findings of CD154-based human cancer therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Altenburg A, Baldus SE, Smola H, Pfister H, Hess S. CD40 ligand-CD40 interaction induces chemokines in cervical carcinoma cells in synergism with IFN-gamma. J Immunol 162:4140–4147;1999.

    PubMed  Google Scholar 

  2. Antonia SJ, Extermann M, Flavell RA. Immunologic nonresponsiveness to tumors. Crit Rev Oncog 9:35–41;1998.

    PubMed  Google Scholar 

  3. Aruffo A, Farrington M, Hollenbaugh D, Li X, Milatovich A, Nonoyama S, Bajorath J, Grosmaire LS, Stenkamp R, Neubauer M. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell 72:291–300;1993.

    Article  PubMed  Google Scholar 

  4. Bennett SR, Carbone FR, Karamalis F, Flavell RA, Miller JF, Health WR. Help for cytotoxic-T-cell responses is mediated by CD40 signalling. Nature 393:478–480;1998.

    Article  PubMed  Google Scholar 

  5. Berberich I, Shu G, Siebelt F, Woodgett JR, Kyriakis JM, Clark EA. Cross-linking CD40 on B cells preferentially induces stress-activated protein kinases rather than mitogen-activated protein kinases. EMBO J 15:92–101;1996.

    PubMed  Google Scholar 

  6. Bergamo A, Bataille R, Pellat-Deceunynck C. CD40 and CD95 induce programmed cell death in the human myeloma cell line XG2. Br J Haematol 97:652–655;1997.

    Article  PubMed  Google Scholar 

  7. Beutler B, van Huffel C. Unraveling function in the TNF ligand and receptor families. Science 264:667–668;1994.

    PubMed  Google Scholar 

  8. Biancone L, Cantaluppi V, Boccellino M, Del Sorbo L, Russo S, Albini A, Stamenkovic I, Camussi G. Activation of CD40 favors the growth and vascularization of Kaposi's sarcoma. J Immunol 163:6201–6208;1999.

    PubMed  Google Scholar 

  9. Biancone L, Cantaluppi V, Camussi G. CD40-CD154 interaction in experimental and human disease (review). Int J Mol Med 3:343–353;1999.

    PubMed  Google Scholar 

  10. Blake GJ, Ostfeld RJ, Yucel EK, Yaro N, Schonbeck U, Blake MA, Gerhard M, Ridker PM, Libby P, Lee RT. Soluble CD40 ligand levels indicate lipid accumulation in carotid atheroma: An in vivo study with high-resolution MRI. Arterioscler Thromb Vasc Biol 23:e11-e14;2003.

    Article  PubMed  Google Scholar 

  11. Bleharski JR, Niazi KR, Sieling PA, Cheng G, Modlin RL. Signaling lymphocytic activation molecule is expressed on CD40 ligand-activated dendritic cells and directly augments production of inflammatory cytokines. J Immunol 167:3174–3181;2001.

    PubMed  Google Scholar 

  12. Borrow P, Tishon A, Lee S, Xu J, Grewal IS, Oldstone MB, Flavell RA. CD40L-deficient mice show deficits in antiviral immunity and have an impaired memory CD8+ CTL response. J Exp Med 183:2129–2142;1996.

    Article  PubMed  Google Scholar 

  13. Briones J, Timmerman J, Levy R. In vivo antitumor effect of CD40L-transduced tumor cells as a vaccine for B-cell lymphoma. Cancer Res 62:3195–3199;2002.

    PubMed  Google Scholar 

  14. Buchner K, Henn V, Grafe M, de Boer OJ, Becker AE, Kroczek RA. CD40 ligand is selectively expressed on CD4+ T cells and platelets: Implications for CD40-CD40L signalling in atherosclerosis. J Pathol 201:288–295;2003.

    Article  PubMed  Google Scholar 

  15. Byrne SN, Halliday GM. Dendritic cells: Making progress with tumour regression? Immunol Cell Biol 80:520–530;2002.

    Article  PubMed  Google Scholar 

  16. Callard RE, Armitage RJ, Fanslow WC, Spriggs MK. CD40 ligand and its role in X-linked hyper-IgM syndrome. Immunol Today 14:559–564;1993.

    Article  PubMed  Google Scholar 

  17. Cantwell MJ, Wierda WG, Lossos IS, Levy R, Kipps TJ. T cell activation following infection of primary follicle center lymphoma B cells with adenovirus encoding CD154. Leukemia 15:1451–1457;2001.

    Article  PubMed  Google Scholar 

  18. Chen HW, Huang HI, Lee YP, Chen LL, Liu HK, Cheng ML, Tsai JP, Tao MH, Ting CC. Linkage of CD40L to a self-tumor antigen enhances the antitumor immune responses of dendritic cell-based treatment. Cancer Immunol Immunother 51:341–348;2002.

    Article  PubMed  Google Scholar 

  19. Chu P, Deforce D, Pedersen IM, Kim Y, Kitada S, Reed JC, Kipps TJ. Latent sensitivity to Fas-mediated apoptosis after CD40 ligation may explain activity of CD154 gene therapy in chronic lymphocytic leukemia. Proc Natl Acad Sci USA 99:3854–3859;2002.

    Article  PubMed  Google Scholar 

  20. Clement MV, Stamenkovic I. Superoxide anion is a natural inhibitor of FAS-mediated cell death. EMBO J 15:216–225;1996.

    PubMed  Google Scholar 

  21. Clodi K, Asgari Z, Younes M, Palmer JL, Cabanillas F, Carbone A, Andreeff M, Younes A. Expression of CD40 ligand (CD154) in B and T lymphocytes of Hodgkin disease: Potential therapeutic significance. Cancer 94:1–5;2002.

    Article  PubMed  Google Scholar 

  22. Costello RT, Gastaut JA, Olive D. What is the real role of CD40 in cancer immunotherapy? Immunol Today 20:488–493;1999.

    Article  PubMed  Google Scholar 

  23. Davis JC Jr, Totoritis MC, Rosenberg J, Sklenar TA, Wofsy D. Phase I clinical trial of a monoclonal antibody against CD40-ligand (IDEC-131) in patients with systemic lupus erythematosus. J Rheumatol 28:95–101;2001.

    PubMed  Google Scholar 

  24. Diehl L, den Boer AT, Schoenberger SP, van der Voort EI, Schumacher TN, Melief CJ, Offringa R, Toes RE. CD40 activation in vivo overcomes peptide-induced peripheral cytotoxic T-lymphocyte tolerance and augments anti-tumor vaccine efficacy. Nat Med 5:774–779;1999.

    Article  PubMed  Google Scholar 

  25. Diehl L, van Mierlo GJ, den Boer AT, van der Voort E, Fransen M, van Bostelen L, Krimpenfort P, Melief CJ, Mittler R, Toes RE, Offringa R. In vivo triggering through 4-1BB enables Th-independent priming of CTL in the presence of an intact CD28 costimulatory pathway. J Immunol 168:3755–3762;2002.

    PubMed  Google Scholar 

  26. Eliopoulos AG, Davies C, Knox PG, Gallagher NJ, Afford SC, Adams DH, Young LS. CD40 induces apoptosis in carcinoma cells through activation of cytotoxic ligands of the tumor necrosis factor superfamily. Mol Cell Biol 20:5503–5515;2000.

    Article  PubMed  Google Scholar 

  27. Eliopoulos AG, Dawson CW, Mosialos G, Floettmann JE, Rowe M, Armitage RJ, Dawson J, Zapata JM, Kerr DJ, Wakelam MJ, Reed JC, Kieff E, Young LS. CD40-induced growth inhibition in epithelial cells is mimicked by Epstein-Barr virus-encoded LMP1: Involvement of TRAF3 as a common mediator. Oncogene 13:2243–2254;1996

    PubMed  Google Scholar 

  28. Elzey BD, Tian J, Jensen RJ, Swanson AK, Lees JR, Lentz SR, Stein CS, Nieswandt B, Wang Y, Davidson BL, Ratliff TL. Plateletmediated modulation of adaptive immunity. A communication link between innate and adaptive immune compartments. Immunity 19:9–19;2003.

    Article  PubMed  Google Scholar 

  29. Eshima K, Mora C, Wong FS, Green EA, Grewal IS, Flavell RA. A crucial role of CD4 T cells as a functional source of CD154 in the initiation of insulin-dependent diabetes mellitus in the non-obese diabetic mouse. Int Immunol 15:351–357;2003.

    Article  PubMed  Google Scholar 

  30. Fidler IJ. Seed and soil revisited: Contribution of the organ microenvironment to cancer metastasis. Surg Oncol Clin N Am 10:257-viiii;2001.

    PubMed  Google Scholar 

  31. Fluckiger AC, Durand I, Banchereau J. Interleukin 10 induces apoptotic cell death of B-chronic lymphocytic leukemia cells. J Exp Med 179:91–99;1994.

    Article  PubMed  Google Scholar 

  32. Freedman JE. CD40-CD40L and platelet function: Beyond hemostasis. Circ Res 92:944–946;2003.

    Article  PubMed  Google Scholar 

  33. Fuentes L, Hernandez M, Fernandez-Aviles FJ, Crespo MS, Nieto ML. Cooperation between secretory phospholipase A2 and TNF-receptor superfamily signaling: Implications for the inflammatory response in atherogenesis. Circ Res 91:681–688;2002.

    Article  PubMed  Google Scholar 

  34. Fuller BW, Nishimura T, Noelle RJ. The selective triggering of CD40 on keratinocytes in vivo enhances cell-mediated immunity. Eur J Immunol 32:895–902;2002.

    Article  PubMed  Google Scholar 

  35. Gabrilovich DI, Chen HL, Girgis KR, Cunningham HT, Meny GM, Nadaf S, Kavanaugh D, Carbone DP. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat Med 2:1096–1103;1996. Erratum in: Nat Med 2:1267;1996.

    Article  PubMed  Google Scholar 

  36. Galibert L, Tometsko ME, Anderson DM, Cosman D, Dougall WC. The involvement of multiple tumor necrosis factor receptor (TNFR)-associated factors in the signaling mechanisms of receptor activator of NF-κB, a member of the TNFR superfamily. J Biol Chem 273:34120–34127;1998.

    Article  PubMed  Google Scholar 

  37. Gauchat JF, Mazzei G, Life P, Henchoz S, Peitsch MC, Aubry JP, Jomotte T, Bonnefoy JY. Human CD40 ligand: Molecular cloning, cellular distribution and regulation of IgE synthesis. Res Immunol 145:240–244;1994.

    Article  PubMed  Google Scholar 

  38. Grammer AC, Swantek JL, McFarland RD, Miura Y, Geppert T, Lipsky PE. TNF receptor-associated factor-3 signaling mediates activation of p38 and Jun N-terminal kinase, cytokine secretion, and Ig production following ligation of CD40 on human B cells. J Immunol 161:1183–1193;1998

    PubMed  Google Scholar 

  39. Grangeon C, Cormary C, Douin-Echinard V, Favre G, Couderc B, Tilkin-Mariame AF. In vivo induction of antitumor immunity and protection against tumor growth by injection of CD154-expressing tumor cells. Cancer Gene Ther 9:282–288;2002.

    Article  PubMed  Google Scholar 

  40. Grewal IS, Borrow P, Pamer EG, Oldstone MB, Flavell RA. The CD40–CD154 system in anti-infective host defense. Curr Opin Immunol 9:491–497;1997.

    Article  PubMed  Google Scholar 

  41. Grewal IS, Flavell RA. A central role of CD40 ligand in the regulation of CD4+ T-cell responses. Immunol Today 17:410–414;1996.

    Article  PubMed  Google Scholar 

  42. Grewal IS, Flavell RA. The role of CD40 ligand in costimulation and T-cell activation. Immunol Rev 153:85–106;1996.

    PubMed  Google Scholar 

  43. Grewal IS, Flavell RA. The CD40 ligand. At the center of the immune universe? Immunol Res 16:59–70;1997.

    PubMed  Google Scholar 

  44. Grewal IS, Foellmer HG, Grewal KD, Xu J, Hardardottir F, Baron JL, Janeway CA Jr, Flavell RA. Requirement for CD40 ligand in costimulation induction, T cell activation, and experimental allergic encephalomyelitis. Science 273:1864–1867;1996.

    PubMed  Google Scholar 

  45. Grewal IS, Xu J, Flavell RA. Impairment of antigen-specific T-cell priming in mice lacking CD40 ligand. Nature 378:617–620;1995.

    Article  PubMed  Google Scholar 

  46. Griebel P, Beskorwayne T, Van den Beskorwayne BA, Ferrari G. CD40 signaling induces B cell responsiveness to multiple members of the gamma chain-common cytokine family. Int Immunol 11:1139–1147;1999.

    Article  PubMed  Google Scholar 

  47. Hanissian SH, Geha RS. Jak3 is associated with CD40 and is critical for CD40 induction of gene expression in B cells. Immunity 6:379–387;1997.

    Article  PubMed  Google Scholar 

  48. Hendriks J, Gravestein LA, Tesselaar K, van Lier RA, Schumacher TN, Borst J. CD27 is required for generation and long-term maintenance of T cell immunity. Nat Immunol 1:433–440;2000.

    Article  PubMed  Google Scholar 

  49. Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, Kroczek RA. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391:591–594;1998.

    Article  PubMed  Google Scholar 

  50. Herold MJ, Kuss AW, Kraus C, Berberich I. Mitochondria-dependent caspase-9 activation is necessary for antigen receptor-mediated effector caspase activation and apoptosis in WEHI 231 lymphoma cells. J Immunol 168:3902–3909;2002.

    PubMed  Google Scholar 

  51. Hess S, Engelmann H. A novel function of CD40: Induction of cell death in transformed cells. J Exp Med 183:159–167;1996.

    Article  PubMed  Google Scholar 

  52. Homann D, Jahreis A, Wolfe T, Hughes A, Coon B, van Stipdonk MJ, Prilliman KR, Schoenberger SP, von Herrath MG. CD40L blockade prevents autoimmune diabetes by induction of bitypic NK/DC regulatory cells. Immunity 16:403–415;2002.

    Article  PubMed  Google Scholar 

  53. Hostager BS, Bishop GA. Cutting edge: Contrasting roles of TNF receptor-associated factor 2 (TRAF2) and TRAF3 in CD40-activated B lymphocyte differentiation. J Immunol 162:6307–6311;1999.

    PubMed  Google Scholar 

  54. Hu BT, Insel RA. Up-regulation of telomerase in human B lymphocytes occurs independently of cellular proliferation and with expression of the telomerase catalytic subunit. Eur J Immunol 29:3745–3753;1999.

    Article  PubMed  Google Scholar 

  55. Inoue S, Egashira K, Ni W, Kitamoto S, Usui M, Otani K, Ishibashi M, Hiasa K, Nishida K, Takeshita A. Anti-monocyte chemoattractant protein-1 gene therapy limits progression and destabilization of established atherosclerosis in apolipoprotein E-knockout mice. Circulation 106:2700–2706;2002.

    Article  PubMed  Google Scholar 

  56. Ishida TK, Tojo T, Aoki T, Kobayashi N, Ohishi T, Watanabe T, Yamamoto T, Inoue J. TRAF5, a novel tumor necrosis factor receptor-associated factor family protein, mediates CD40 signaling. Proc Natl Acad Sci USA 93:9437–9442;1996.

    Article  PubMed  Google Scholar 

  57. Janeway CA Jr, Bottomly K. Signals and signs for lymphocyte responses. Cell 76:275–285;1994.

    Article  PubMed  Google Scholar 

  58. Johnson PW, Watt SM, Betts DR, Davies D, Jordan S, Norton AJ, Lister TA. Isolated follicular lymphoma cells are resistant to apoptosis and can be grown in vitro in the CD40/stromal cell system. Blood 82:1848–1857;1993.

    PubMed  Google Scholar 

  59. Kiener PA, Moran-Davis P, Rankin BM, Wahl AF, Aruffo A, Hollenbaugh D. Stimulation of CD40 with purified soluble gp39 induces proinflammatory responses in human monocytes. J Immunol 155:4917–4925;1995.

    PubMed  Google Scholar 

  60. Kipps TJ, Chu P, Wierda WG. Immunogenetic therapy for B-cell malignancies. Semin Oncol 27:104–109;2000.

    PubMed  Google Scholar 

  61. Kluin-Nelemans HC, Beverstock GC, Mollevanger P, Wessels HW, Hoogendoorn E, Willemze R, Falkenburg JH. Proliferation and cytogenetic analysis of hairy cell leukemia upon stimulation via the CD40 antigen. Blood 84:3134–3141;1994.

    PubMed  Google Scholar 

  62. Kover KL, Geng Z, Hess DM, Benjamin CD, Moore WV. Anti-CD154 (CD40L) prevents recurrence of diabetes in islet isografts in the DR-BB rat. Diabetes 49:1666–1670;2000.

    PubMed  Google Scholar 

  63. Laman JD, de Smet BJ, Schoneveld A, Van Meurs M. CD40-CD40L interactions in atherosclerosis. Immunol Today 18:272–277;1997.

    Article  PubMed  Google Scholar 

  64. Liu Y, Qureshi M, Xiang J. Antitumor immune responses derived from transgenic expression of CD40 ligand in myeloma cells. Cancer Biother Radiopharm 17:11–18;2002.

    Article  PubMed  Google Scholar 

  65. Liu Y, Zhang X, Zhang W, Chen Z, Chan T, Ali K, Jia Z, Xiang J. Adenovirus-mediated CD40 ligand gene-engineered dendritic cells elicit enhanced CD8(+) cytotoxic T-cell activation and antitumor immunity. Cancer Gene Ther 9:202–208;2002.

    Article  PubMed  Google Scholar 

  66. Lutgens E, Cleutjens KB, Heeneman S, Koteliansky VE, Burkly LC, Daemen MJ. Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype. Proc Natl Acad Sci USA 97:7464–7469;2000.

    Article  PubMed  Google Scholar 

  67. Lutgens E, Daemen MJ. CD40-CD40L interactions in atherosclerosis. Trends Cardiovasc Med 12:27–32;2002.

    Article  PubMed  Google Scholar 

  68. Lutgens E, Gorelik L, Daemen MJ, de Muinck ED, Grewal IS, Koteliansky VE, Flavell RA. Requirement for CD154 in the progression of atherosclerosis. Nat Med 5:1313–1316;1999.

    Article  PubMed  Google Scholar 

  69. Mach F, Schonbeck U, Libby P. CD40 signaling in vascular cells: A key role in atherosclerosis? Atherosclerosis 137(suppl):S89-S95;1998.

    Article  PubMed  Google Scholar 

  70. Mach F, Schonbeck U, Sukhova GK, Atkinson E, Libby P. Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature 394:200–203;1998.

    Article  PubMed  Google Scholar 

  71. Mackey MF, Gunn JR, Ting PP, Kikutani H, Dranoff G, Noelle RJ, Barth RJ Jr. Protective immunity induced by tumor vaccines requires interaction between CD40 and its ligand, CD154. Cancer Res 57:2569–2574;1997.

    PubMed  Google Scholar 

  72. Marches R, Racila E, Tucker TF, Picker L, Mongini P, Hsueh R, Vitetta ES, Scheuermann RH, Uhr JW. Tumour dormancy and cell signalling — III: Role of hypercrosslinking of IgM and CD40 on the induction of cell cycle arrest and apoptosis in B lymphoma cells. Ther Immunol 2:125–136;1995.

    PubMed  Google Scholar 

  73. Molano RD, Berney T, Li H, Cattan P, Pileggi A, Vizzardelli C, Kenyon NS, Ricordi C, Burkly LC, Inverardi L. Prolonged islet graft survival in NOD mice by blockade of the CD40–CD154 pathway of T-cell costimulation. Diabetes 50:270–276;2001.

    PubMed  Google Scholar 

  74. Moore WV, Chu W, Tong PY, Hess D, Benjamin C, Khalili J, Kover K. Prevention of autoimmune diabetes in the DRBB rat by CD40/154 blockade. J Autoimmun 19:139–145;2002.

    Article  PubMed  Google Scholar 

  75. Murphy WJ, Welniak L, Back T, Hixon J, Subleski J, Seki N, Wigginton JM, Wilson SE, Blazar BR, Malyguine AM, Sayers TJ, Wiltrout RH. Synergistic anti-tumor responses after administration of agonistic antibodies to CD40 and IL-2: Coordination of dendritic and CD8+cell responses. J Immunol 170:2727–2733;2003.

    PubMed  Google Scholar 

  76. Nannizzi-Alaimo L, Alves VL, Phillips DR. Inhibitory effects of glycoprotein IIb/IIIa antagonists and aspirin on the release of soluble CD40 ligand during platelet stimulation. Circulation 107:1123–1128;2003.

    Article  PubMed  Google Scholar 

  77. Nguyen VT, Benveniste EN. Critical role of tumor necrosis factor-alpha and NF-kappa B in interferon-gamma -induced CD40 expression in microglia/macrophages. J Biol Chem 277:13796–13803;2002.

    Article  PubMed  Google Scholar 

  78. Ni CZ, Welsh K, Leo E, Chiou CK, Wu H, Reed JC, Ely KR. Molecular basis for CD40 signaling mediated by TRAF3. Proc Natl Acad Sci USA 97:10395–10399;2000.

    Article  PubMed  Google Scholar 

  79. O'Sullivan BJ, Thomas R. CD40 ligation conditions dendritic cell antigen-presenting function through sustained activation of NF-κB. J Immunol 168:5491–5498;2002.

    PubMed  Google Scholar 

  80. Osada T, Nagawa H, Takahashi T, Tsuno NH, Kitayama J, Shibata Y. Dendritic cells cultured in anti-CD40 antibody-immobilized plates elicit a highly efficient peptide-specific T-cell response. J Immunother 25:176–184;2002.

    Article  PubMed  Google Scholar 

  81. Oxenius A, Campbell KA, Maliszewski CR, Kishimoto T, Kikutani H, Hengartner H, Zinkernagel RM, Bachmann MF. CD40-CD40 ligand interactions are critical in T-B cooperation but not for other anti-viral CD4+ T cell functions. J Exp Med 183:2209–2218;1996.

    Article  PubMed  Google Scholar 

  82. Pearson LL, Castle BE, Kehry MR. CD40-mediated signaling in monocytic cells: Up-regulation of tumor necrosis factor receptor-associated factor mRNAs and activation of mitogen-activated protein kinase signaling pathways. Int Immunol 13:273–283;2001.

    Article  PubMed  Google Scholar 

  83. Perez-Melgosa M, Hollenbaugh D, Wilson CB. Cutting edge: CD40 ligand is a limiting factor in the humoral response to T cell-dependent antigens. J Immunol 163:1123–1127;1999.

    PubMed  Google Scholar 

  84. Pullen SS, Labadia ME, Ingraham RH, McWhirter SM, Everdeen DS, Alber T, Crute JJ, Kehry MR. High-affinity interactions of tumor necrosis factor receptor-associated factors (TRAFs) and CD40 require TRAF trimerization and CD40 multimerization. Biochemistry 38:10168–10177;1999.

    Article  PubMed  Google Scholar 

  85. Rathmell JC, Townsend SE, Xu JC, Flavell RA, Goodnow CC. Expansion or elimination of B cells in vivo: Dual roles for CD40- and Fas (CD95)-ligands modulated by the B cell antigen receptor. Cell 87:319–329;1996.

    Article  PubMed  Google Scholar 

  86. Razanajaona D, van Kooten C, Lebecque S, Bridon JM, Ho S, Smith S, Callard R, Banchereau J, Briere F. Somatic mutations in human Ig variable genes correlate with a partially functional CD40-ligand in the X-linked hyper-IgM syndrome. J Immunol 157:1492–1498;1996.

    PubMed  Google Scholar 

  87. Ribas A, Butterfield LH, Amarnani SN, Dissette VB, Kim D, Meng WS, Miranda GA, Wang HJ, McBride WH, Glaspy JA, Economou JS. CD40 cross-linking bypasses the absolute requirement for CD4 T cells during immunization with melanoma antigen gene-modified dendritic cells. Cancer Res 61:8787–8793;2001.

    PubMed  Google Scholar 

  88. Ross R. The pathogenesis of atherosclerosis — An update. N Engl J Med 314:488–500;1986.

    PubMed  Google Scholar 

  89. Roy M, Aruffo A, Ledbetter J, Linsley P, Kehry M, Noelle R. Studies on the interdependence of gp39 and B7 expression and function during antigen-specific immune responses. Eur J Immunol 25:596–603;1995.

    Google Scholar 

  90. Schattner EJ, Mascarenhas J, Bishop J, Yoo DH, Chadburn A, Crow MK, Friedman SM. CD4+ T-cell induction of Fas-mediated apoptosis in Burkitt's lymphoma B cells. Blood 88:1375–1382;1996.

    PubMed  Google Scholar 

  91. Schoenberger SP, Toes RE, van der Voort EI, Offringa R, Melief CJ. T-cell help for cytotoxic T lymphocytes is mediated by CD40–CD40L interactions. Nature 393:480–483;1998.

    Article  PubMed  Google Scholar 

  92. Schonbeck U, Sukhova GK, Shimizu K, Mach F, Libby P. Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. Proc Natl Acad Sci USA 97:7458–7463;2000.

    Article  PubMed  Google Scholar 

  93. Schultze JL, Anderson KC, Gilleece MH, Gribben JG, Nadler LM. A pilot study of combined immunotherapy with autologous adoptive tumour-specific T-cell transfer, vaccination with CD40-activated malignant B cells and interleukin 2. Br J Haematol 113:455–460;2001.

    Article  PubMed  Google Scholar 

  94. Seyama K, Nonoyama S, Gangsaas I, Hollenbaugh D, Pabst HF, Aruffo A, Ochs HD. Mutations of the CD40 ligand gene and its effect on CD40 ligand expression in patients with X-linked hyper IgM syndrome. Blood 92:2421–2434;1998.

    PubMed  Google Scholar 

  95. Shinde S, Wu Y, Guo Y, Niu Q, Xu J, Grewal IS, Flavell R, Liu Y. CD40L is important for induction of, but not response to, costimulatory activity. ICAM-1 as the second costimulatory molecule rapidly up-regulated by CD40L. J Immunol 157:2764–2768;1996.

    PubMed  Google Scholar 

  96. Sin JI, Kim JJ, Zhang D, Weiner DB. Modulation of cellular responses by plasmid CD40L: CD40L plasmid vectors enhance antigen-specific helper T cell type 1 CD4+ T cell-mediated protective immunity against herpes simplex virus type 2 in vivo. Hum Gene Ther 12:1091–1102;2001.

    Article  PubMed  Google Scholar 

  97. Singh SR, Casper K, Summers S, Swerlick RA. CD40 expression and function on human dermal microvascular endothelial cells: Role in cutaneous inflammation. Clin Exp Dermatol 26:434–440;2001.

    Article  PubMed  Google Scholar 

  98. Sugimoto K, Galle C, Preiser JC, Creteur J, Vincent JL, Pradier O. Monocyte CD40 expression in severe sepsis. Shock 19:24–27;2003.

    Article  PubMed  Google Scholar 

  99. Teoh G, Tai YT, Urashima M, Shirahama S, Matsuzaki M, Chauhan D, Treon SP, Raje N, Hideshima T, Shima Y, Anderson KC. CD40 activation mediates p53-dependent cell cycle regulation in human multiple myeloma cell lines. Blood 95:1039–1046;2000.

    PubMed  Google Scholar 

  100. Tolba KA, Bowers WJ, Hilchey SP, Halterman MW, Howard DF, Giuliano RE, Federoff HJ, Rosenblatt JD. Development of herpes simplex virus-1 amplicon-based immunotherapy for chronic lymphocytic leukemia. Blood 98:287–295;2001.

    Article  PubMed  Google Scholar 

  101. Tone M, Tone Y, Fairchild PJ, Wykes M, Waldmann H. Regulation of CD40 function by its isoforms generated through alternative splicing. Proc Natl Acad Sci USA 98:1751–1756;2001.

    Article  PubMed  Google Scholar 

  102. Tong AW, Papayoti MH, Netto G, Armstrong DT, Ordonez G, Lawson JM, Stone MJ. Growth-inhibitory effects of CD40 ligand (CD154) and its endogenous expression in human breast cancer. Clin Cancer Res 7:691–703;2001.

    PubMed  Google Scholar 

  103. Tsukamoto N, Kobayashi N, Azuma S, Yamamoto T, Inoue J. Two differently regulated nuclear factor κB activation pathways triggered by the cytoplasmic tail of CD40. Proc Natl Acad Sci USA 96:1234–1239;1999.

    Article  PubMed  Google Scholar 

  104. van Kooten C, Banchereau J. CD40-CD40 ligand. J Leukoc Biol 67:2–17;2000.

    PubMed  Google Scholar 

  105. van Mierlo GJ, den Boer AT, Medema JP, van der Voort EI, Fransen MF, Offringa R, Melief CJ, Toes RE. CD40 stimulation leads to effective therapy of CD40(-) tumors through induction of strong systemic cytotoxic T lymphocyte immunity. Proc Natl Acad Sci USA 99:5561–5566;2002.

    Article  PubMed  Google Scholar 

  106. Vonderheide RH, Dutcher JP, Anderson JE, Eckhardt SG, Stephans KF, Razvillas B, Garl S, Butine MD, Perry VP, Armitage RJ, Ghalie R, Caron DA, Gribben JG. Phase I study of recombinant human CD40 ligand in cancer patients. J Clin Oncol 19:3280–3287;2001.

    PubMed  Google Scholar 

  107. Wagner DH Jr, Vaitaitis G, Sanderson R, Poulin M, Dobbs C, Haskins K. Expression of CD40 identifies a unique pathogenic T cell population in type 1 diabetes. Proc Natl Acad Sci USA 99:3782–3787;2002.

    Article  PubMed  Google Scholar 

  108. Wang CY, Mayo MW, Korneluk RG, Goeddel DV, Baldwin AS Jr. NF-κB antiapoptosis: Induction of TRAF1 and TRAF2 and c-IAP1 and c-IAP2 to suppress caspase-8 activation. Science 281:1680–1683;1998.

    PubMed  Google Scholar 

  109. Werneburg BG, Zoog SJ, Dang TT, Kehry MR, Crute JJ. Molecular characterization of CD40 signaling intermediates. J Biol Chem 276:43334–43342;2001.

    Article  PubMed  Google Scholar 

  110. Wierda WG, Cantwell MJ, Woods SJ, Rassenti LZ, Prussak CE, Kipps TJ. CD40-ligand (CD154) gene therapy for chronic lymphocytic leukemia. Blood 96:2917–2924;2000.

    PubMed  Google Scholar 

  111. Wurtzen PA, Nissen MH, Claesson MH. Maturation of dendritic cells by recombinant human CD40L-trimer leads to a homogeneous cell population with enhanced surface marker expression and increased cytokine production. Scand J Immunol 53:579–587;2001.

    Article  PubMed  Google Scholar 

  112. Yamada M, Shiroko T, Kawaguchi Y, Sugiyama Y, Egilmez NK, Chen FA, Bankert RB. CD40-CD40 ligand (CD154) engagement is required but not sufficient for modulating MHC class I, ICAM-1 and Fas expression and proliferation of human non-small cell lung tumors. Int J Cancer 92:589–599;2001.

    Article  PubMed  Google Scholar 

  113. Yang Y, Su Q, Grewal IS, Schilz R, Flavell RA, Wilson JM. Transient subversion of CD40 ligand function diminishes immune responses to adenovirus vectors in mouse liver and lung tissues. J Virol 70:6370–6377;1996.

    PubMed  Google Scholar 

  114. Younes A. CD40 ligand therapy of lymphoma patients. J Clin Oncol 19:4351–4353;2001.

    PubMed  Google Scholar 

  115. Zapata JM, Krajewska M, Krajewski S, Kitada S, Welsh K, Monks A, McCloskey N, Gordon J, Kipps TJ, Gascoyne RD, Shabaik A, Reed JC. TNFR-associated factor family protein expression in normal tissues and lymphoid malignancies. J Immunol 165:5084–5096;2000.

    PubMed  Google Scholar 

  116. Ziebold JL, Hixon J, Boyd A, Murphy WJ. Differential effects of CD40 stimulation on normal and neoplastic cell growth. Arch Immunol Ther Exp (Warsz) 48:225–233;2000.

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Xu, Y., Song, G. The role of CD40-CD154 interaction in cell immunoregulation. J Biomed Sci 11, 426–438 (2004). https://doi.org/10.1007/BF02256091

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02256091

Key Words

Navigation