Tuning of CD40–CD154 Interactions in Human B-Lymphocyte Activation: A Broad Array of In Vitro Models for a Complex In Vivo Situation

  • Sonia NéronEmail author
  • Philippe J. Nadeau
  • André Darveau
  • Jean-François Leblanc


Naive and memory B-lymphocyte populations can be activated through the binding of CD154 to CD40, a receptor that is constitutively expressed on the surface of these cells. Models based on the in vitro stimulation of human B lymphocytes through CD40 have greatly contributed to our understanding of the human immune response in healthy individuals and patients suffering from immune disorders. The nature of the engineered CD40 ligands is as diverse as the in vitro models used in studies of CD40-activated B lymphocytes. Monoclonal anti-CD40 antibodies, recombinant CD154 proteins, soluble CD154+ membranes as well as CD154+ cell lines have turned out to be very useful tools, and are still in use today. As for any receptor–ligand interaction, parameters such as duration and strength of contact, timing, affinity, and receptor density are major determinants of CD40 binding by CD154 or anti-CD40. Furthermore, variation in the intensity of CD40 stimulation has been shown to influence proliferation, differentiation and immunoglobulin secretion of human hybridomas, B-cell lines, tonsil and blood B lymphocytes. The objective of this review is to present an overview of the great diversity of CD40 agonists used in in vitro models of B-lymphocyte activation, with a particular emphasis on variations in the resulting strength of CD40 signaling generated by these models. A better understanding of these models could open up new avenues for the rational use of human B lymphocytes as antigen-presenting cells in cellular therapies.


CD40–CD154 intensity B lymphocytes In vitro models 



Phorbol 12-myristate 13-acetate


  1. Andersen NS, Larsen JK, Christiansen J et al (2000) Soluble CD40 ligand induces selective proliferation of lymphoma cells in primary mantle cell lymphoma cell cultures. Blood 96:2219–2225PubMedGoogle Scholar
  2. Andre P, Nannizzi-Alaimo L, Prasad SK et al (2002) Platelet-derived CD40L: the switch-hitting player of cardiovascular disease. Circulation 106:896–899PubMedGoogle Scholar
  3. Armitage RJ, Fanslow WC, Strockbine L et al (1992) Molecular and biological characterization of a murine ligand for CD40. Nature 357:80–82PubMedGoogle Scholar
  4. Arpin C, Dechanet J, Van Kooten C et al (1995) Generation of memory B cells and plasma cells in vitro. Science 268:720–722PubMedGoogle Scholar
  5. Arpin C, Banchereau J, Liu YJ (1997) Memory B cells are biased towards terminal differentiation: a strategy that may prevent repertoire freezing. J Exp Med 186:931–940PubMedGoogle Scholar
  6. Avery DT, Bryant VL, Ma CS et al (2008a) IL-21-induced isotype switching to IgG and IgA by human naive B cells is differentially regulated by IL-4. J Immunol 181:1767–1779PubMedGoogle Scholar
  7. Avery DT, Ma CS, Bryant VL et al (2008b) STAT3 is required for IL-21-induced secretion of IgE from human naive B cells. Blood 112:1784–1793PubMedGoogle Scholar
  8. Baker MP, Eliopoulos AG, Young LS et al (1998) Prolonged phenotypic, functional, and molecular change in group I Burkitt lymphoma cells on short-term exposure to CD40 ligand. Blood 92:2830–2843PubMedGoogle Scholar
  9. Banchereau J, Rousset F (1991) Growing human B lymphocytes in the CD40 system. Nature 353:678–679PubMedGoogle Scholar
  10. Banchereau J, de Paoli P, Valle A et al (1991) Long-term human B cell lines dependent on interleukin-4 and antibody to CD40. Science 251:70–72PubMedGoogle Scholar
  11. Banchereau J, Bazan F, Blanchard D et al (1994) The CD40 antigen and its ligand. Annu Rev Immunol 12:881–922PubMedGoogle Scholar
  12. Banchereau J, Briere F, Caux C et al (2000) Immunobiology of dendritic cells. Annu Rev Immunol 18:767–811PubMedGoogle Scholar
  13. Barcia C, Gomez A, de Pablos V et al (2008) CD20, CD3, and CD40 ligand microclusters segregate three-dimensionally in vivo at B-cell-T-cell immunological synapses after viral immunity in primate brain. J Virol 82:9978–9993PubMedGoogle Scholar
  14. Barr TA, Heath AW (2001) Functional activity of CD40 antibodies correlates to the position of binding relative to CD154. Immunology 102:39–43PubMedGoogle Scholar
  15. Batista FD, Iber D, Neuberger MS (2001) B cells acquire antigen from target cells after synapse formation. Nature 411:489–494PubMedGoogle Scholar
  16. Batlle A, Papadopoulou V, Gomes AR et al (2009) CD40 and B-cell receptor signalling induce MAPK family members that can either induce or repress Bcl-6 expression. Mol Immunol 46:1727–1735PubMedGoogle Scholar
  17. Bishop GA, Hostager BS (2003) The CD40–CD154 interaction in B cell-T cell liaisons. Cytokine Growth Factor Rev 14:297–309PubMedGoogle Scholar
  18. Bishop GA, Moore CR, Xie P et al (2007) TRAF proteins in CD40 signaling. Adv Exp Med Biol 597:131–151PubMedGoogle Scholar
  19. Bjorck P, Paulie S (1996) CD40 antibodies defining distinct epitopes display qualitative differences in their induction of B-cell differentiation. Immunology 87:291–295PubMedGoogle Scholar
  20. Boisvert J, Edmondson S, Krummel MF (2004) Immunological synapse formation licenses CD40-CD40L accumulations at T-APC contact sites. J Immunol 173:3647–3652PubMedGoogle Scholar
  21. Brian AA (1988) Stimulation of B-cell proliferation by membrane-associated molecules from activated T cells. Proc Natl Acad Sci USA 85:564–568PubMedGoogle Scholar
  22. Burdin N, Van Kooten C, Galibert L et al (1995) Endogenous IL-6 and IL-10 contribute to the differentiation of CD40-activated human B lymphocytes. J Immunol 154:2533–2544PubMedGoogle Scholar
  23. Burdin N, Galibert L, Garrone P et al (1996) Inability to produce IL-6 is a functional feature of human germinal center B lymphocytes. J Immunol 156:4107–4113PubMedGoogle Scholar
  24. Casamayor-Palleja M, Khan M, MacLennan IC (1995) A subset of CD4+ memory T cells contains preformed CD40 ligand that is rapidly but transiently expressed on their surface after activation through the T cell receptor complex. J Exp Med 181:1293–1301PubMedGoogle Scholar
  25. Castle BE, Kishimoto K, Stearns C et al (1993) Regulation of expression of the ligand for CD40 on T helper lymphocytes. J Immunol 151:1777–1788PubMedGoogle Scholar
  26. Cayer MP, Drouin M, Sea SP et al (2007) Comparison of promoter activities for efficient expression into human B cells and haematopoietic progenitors with adenovirus Ad5/F35. J Immunol Methods 322:118–127PubMedGoogle Scholar
  27. Cayer MP, Proulx M, Ma XZ et al (2009) c-Src tyrosine kinase co-associates with and phosphorylates signal transducer and activator of transcription 5b which mediates the proliferation of normal human B lymphocytes. Clin Exp Immunol 156:419–427PubMedGoogle Scholar
  28. Challa A, Eliopoulos AG, Holder MJ et al (2002) Population depletion activates autonomous CD154-dependent survival in biopsylike Burkitt lymphoma cells. Blood 99:3411–3418PubMedGoogle Scholar
  29. Choe J, Choi YS (1998) IL-10 interrupts memory B cell expansion in the germinal center by inducing differentiation into plasma cells. Eur J Immunol 28:508–515PubMedGoogle Scholar
  30. Choe J, Kim HS, Zhang X et al (1996) Cellular and molecular factors that regulate the differentiation and apoptosis of germinal center B cells. Anti-Ig down-regulates Fas expression of CD40 ligand-stimulated germinal center B cells and inhibits Fas-mediated apoptosis. J Immunol 157:1006–1016PubMedGoogle Scholar
  31. Clark EA, Ledbetter JA (1986) Activation of human B cells mediated through two distinct cell surface differentiation antigens, Bp35 and Bp50. Proc Natl Acad Sci USA 83:4494–4498PubMedGoogle Scholar
  32. Clark EA, Shu G (1990) Association between IL-6 and CD40 signaling. IL-6 induces phosphorylation of CD40 receptors. J Immunol 145:1400–1406PubMedGoogle Scholar
  33. Cognasse F, Hameh-Cognasse H, Lafarge S et al (2007) Human platelets can activate peripheral blood B cells and increase production of immunoglobulins. Exp Hematol 35:1376–1387PubMedGoogle Scholar
  34. Costello RT, Gastaut JA, Olive D (1999) What is the real role of CD40 in cancer immunotherapy? Immunol Today 20:488–493PubMedGoogle Scholar
  35. Darveau A, Chevrier MC, Néron S et al (1993) Efficient preparation of human monoclonal antibody-secreting heterohybridomas using peripheral B lymphocytes cultured in the CD40 system. J Immunol Methods 159:139–143PubMedGoogle Scholar
  36. Davis DM (2009) Mechanisms and functions for the duration of intercellular contacts made by lymphocytes. Nat Rev Immunol 9:543–555PubMedGoogle Scholar
  37. De Paoli P, Cozzi M, Tedeschi R et al (1997) High CD40 membrane expression in AIDS-related lymphoma B cell lines is associated with the CD45RA+, CD45RO+, CD95+ phenotype and high levels of its soluble form in culture supernatants. Cytometry 30:33–38PubMedGoogle Scholar
  38. Desai-Mehta A, Lu L, Ramsey-Goldman R et al (1996) Hyperexpression of CD40 ligand by B and T cells in human lupus and its role in pathogenic autoantibody production. J Clin Invest 97:2063–2073PubMedGoogle Scholar
  39. Devi BS, Van Noordin S, Krausz T et al (1998) Peripheral blood lymphocytes in SLE–hyperexpression of CD154 on T and B lymphocytes and increased number of double negative T cells. J Autoimmun 11:471–475PubMedGoogle Scholar
  40. Ducas E, Dussault N, Roy A et al (2009) Estimation of the number of CD154 molecules in membrane extracts used as a source of CD40 stimulation of human B lymphocytes. J Immunol Methods 344:133–137PubMedGoogle Scholar
  41. Elgueta R, Benson MJ, de Vries VC et al (2009) Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev 229:152–172PubMedGoogle Scholar
  42. Elmetwali T, Young LS, Palmer DH (2010) CD40 ligand-induced carcinoma cell death: a balance between activation of TNFR-associated factor (TRAF) 3-dependent death signals and suppression of TRAF6-dependent survival signals. J Immunol 184:1111–1120PubMedGoogle Scholar
  43. Eris JM, Basten A, Brink R et al (1994) Anergic self-reactive B cells present self antigen and respond normally to CD40-dependent T-cell signals but are defective in antigen-receptor-mediated functions. Proc Natl Acad Sci USA 91:4392–4396PubMedGoogle Scholar
  44. Fanslow WC, Srinivasan S, Paxton R et al (1994) Structural characteristics of CD40 ligand that determine biological function. Semin Immunol 6:267–278PubMedGoogle Scholar
  45. Fayette J, Dubois B, Caux C et al (1995) Human dendritic cells can drive CD40-activated sIgD+ B cells to mount mucosal-type humoral response. Adv Exp Med Biol 378:401–403PubMedGoogle Scholar
  46. Fecteau JF, Néron S (2003) CD40 stimulation of human peripheral B lymphocytes: distinct response from naïve and memory cells. J Immunol 171:4621–4629PubMedGoogle Scholar
  47. Fecteau JF, Côté G, Néron S (2006) A new memory CD27IgG+ B cell population in peripheral blood expressing VH genes with low frequency of somatic mutation. J Immunol 177:3728–3736PubMedGoogle Scholar
  48. Fecteau JF, Roy A, Neron S (2009) Peripheral blood CD27(+) IgG(+) B cells rapidly proliferate and differentiate into immunoglobulin-secreting cells after exposure to low CD154 interaction. Immunology 128(suppl 1):e353–e365PubMedGoogle Scholar
  49. Ford GS, Barnhart B, Shone S et al (1999) Regulation of CD154 (CD40 ligand) mRNA stability during T cell activation. J Immunol 162:4037–4044PubMedGoogle Scholar
  50. French LE, Huard B, Wysocka M et al (2005) Impaired CD40L signaling is a cause of defective IL-12 and TNF-alpha production in Sezary syndrome: circumvention by hexameric soluble CD40L. Blood 105:219–225PubMedGoogle Scholar
  51. Friedl P, den Boer AT, Gunzer M (2005) Tuning immune responses: Diversity and adaptation of the immunological synapse. Nat Rev Immunol 5:532–545PubMedGoogle Scholar
  52. Friman V, Hanson LA, Bridon JM et al (1996) IL-10-driven immunoglobulin production by B lymphocytes from IgA-deficient individuals correlates to infection proneness. Clin Exp Immunol 104:432–438PubMedGoogle Scholar
  53. Galibert L, Durand I, Banchereau J et al (1994) CD40-activated surface IgD-positive lymphocytes constitute the long term IL-4-dependent proliferating B cell pool. J Immunol 152:22–29PubMedGoogle Scholar
  54. Galibert L, van Dooren J, Durand I et al (1995) Anti-CD40 plus interleukin-4-activated human naive B cell lines express unmutated immunoglobulin genes with intraclonal heavy chain isotype variability. Eur J Immunol 25:733–737PubMedGoogle Scholar
  55. Galibert L, Burdin N, Barthelemy C et al (1996) Negative selection of human germinal center B cells by prolonged BCR cross-linking. J Exp Med 183:2075–2085PubMedGoogle Scholar
  56. Garrone P, Neidhardt EM, Garcia E et al (1995) Fas ligation induces apoptosis of CD40-activated human B lymphocytes. J Exp Med 182:1265–1273PubMedGoogle Scholar
  57. Gauchat JF, Aubry JP, Mazzei G et al (1993) Human CD40-ligand: molecular cloning, cellular distribution and regulation of expression by factors controlling IgE production. FEBS Lett 315:259–266PubMedGoogle Scholar
  58. Good KL, Avery DT, Tangye SG (2009) Resting human memory B cells are intrinsically programmed for enhanced survival and responsiveness to diverse stimuli compared to naive B cells. J Immunol 182:890–901PubMedGoogle Scholar
  59. Gordon J (1991) Human B lymphocytes mature. Clin Exp Immunol 84:373–375PubMedGoogle Scholar
  60. Gordon J (1995) CD40 and its ligand: central players in B lymphocyte survival, growth, and differentiation. Blood Rev 9:53–56PubMedGoogle Scholar
  61. Gordon J, Pound JD (2000) Fortifying B cells with CD154: an engaging tale of many hues. Immunology 100:269–280PubMedGoogle Scholar
  62. Gordon J, Millsum MJ, Guy GR et al (1988) Resting B lymphocytes can be triggered directly through the CDw40 (Bp50) antigen. A comparison with IL-4-mediated signaling. J Immunol 140:1425–1430PubMedGoogle Scholar
  63. Goules A, Tzioufas AG, Manousakis MN et al (2006) Elevated levels of soluble CD40 ligand (sCD40L) in serum of patients with systemic autoimmune diseases. J Autoimmun 26:165–171PubMedGoogle Scholar
  64. Graf D, Muller S, Korthauer U et al (1995) A soluble form of TRAP (CD40 ligand) is rapidly released after T cell activation. Eur J Immunol 25:1749–1754PubMedGoogle Scholar
  65. Grammer AC, Lipsky PE (2001) CD40-mediated regulation of immune responses by TRAF-dependent and TRAF-independent signaling mechanisms. Adv Immunol 76:61–178Google Scholar
  66. Grammer AC, Lipsky PE (2002) CD154–CD40 interactions mediate differentiation to plasma cells in healthy individuals and persons with systemic lupus erythematosus. Arthritis Rheum 46:1417–1429PubMedGoogle Scholar
  67. Grammer AC, Slota R, Fischer R et al (2003) Abnormal germinal center reactions in systemic lupus erythematosus demonstrated by blockade of CD154–CD40 interactions. J Clin Invest 112:1506–1520PubMedGoogle Scholar
  68. Grewal IS, Flavell RA (1998) CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol 16:111–135PubMedGoogle Scholar
  69. Gruber MF, Bjorndahl JM, Nakamura S et al (1989) Anti-CD45 inhibition of human B cell proliferation depends on the nature of activation signals and the state of B cell activation. A study with anti-IgM and anti-CDw40 antibodies. J Immunol 142:4144–4152PubMedGoogle Scholar
  70. Hasbold J, Lyons AB, Kehry MR et al (1998) Cell division number regulates IgG1 and IgE switching of B cells following stimulation by CD40 ligand and IL-4. Eur J Immunol 28:1040–1051PubMedGoogle Scholar
  71. Hasbold J, Hong JS, Kehry MR et al (1999) Integrating signals from IFN-gamma and IL-4 by B cells: positive and negative effects on CD40 ligand-induced proliferation, survival, and division-linked isotype switching to IgG1, IgE, and IgG2a. J Immunol 163:4175–4181PubMedGoogle Scholar
  72. Hassan GS, Merhi Y, Mourad WM (2009) CD154 and its receptors in inflammatory vascular pathologies. Trends Immunol 30:165–172PubMedGoogle Scholar
  73. Haswell LE, Glennie MJ, Al-Shamkhani A (2001) Analysis of the oligomeric requirement for signaling by CD40 using soluble multimeric forms of its ligand, CD154. Eur J Immunol 31:3094–3100PubMedGoogle Scholar
  74. Heidt S, Roelen DL, Eijsink C et al (2009) Intravenous immunoglobulin preparations have no direct effect on B cell proliferation and immunoglobulin production. Clin Exp Immunol 158:99–105PubMedGoogle Scholar
  75. Henn V, Steinbach S, Buchner K et al (2001) The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by coexpressed CD40. Blood 98:1047–1054PubMedGoogle Scholar
  76. Hirano A, Longo DL, Taub DD et al (1999) Inhibition of human breast carcinoma growth by a soluble recombinant human CD40 ligand. Blood 93:2999–3007PubMedGoogle Scholar
  77. Hodgkin PD, Yamashita LC, Coffman RL et al (1990) Separation of events mediating B cell proliferation and Ig production by using T cell membranes and lymphokines. J Immunol 145:2025–2034PubMedGoogle Scholar
  78. Hodgkin PD, Yamashita LC, Seymour B et al (1991) Membranes from both Th1 and Th2 T cell clones stimulate B cell proliferation and prepare B cells for lymphokine-induced differentiation to secrete Ig. J Immunol 147:3696–3702PubMedGoogle Scholar
  79. Hollenbaugh D, Grosmaire LS, Kullas CD et al (1992) The human T cell antigen gp39, a member of the TNF gene family, is a ligand for the CD40 receptor: expression of a soluble form of gp39 with B cell co-stimulatory activity. EMBO J 11:4313–4321PubMedGoogle Scholar
  80. Hostager BS (2007) Roles of TRAF6 in CD40 signaling. Immunol Res 39:105–114PubMedGoogle Scholar
  81. Ivanov R, Aarts T, Hagenbeek A et al (2005) B-cell expansion in the presence of the novel 293-CD40L-sCD40L cell line allows the generation of large numbers of efficient xenoantigen-free APC. Cytotherapy 7:62–73PubMedGoogle Scholar
  82. Jabara HH, Fu SM, Geha RS et al (1990) CD40 and IgE: synergism between anti-CD40 monoclonal antibody and interleukin 4 in the induction of IgE synthesis by highly purified human B cells. J Exp Med 172:1861–1864PubMedGoogle Scholar
  83. Jaiswal AI, Croft M (1997) CD40 ligand induction on T cell subsets by peptide-presenting B cells: implications for development of the primary T and B cell response. J Immunol 159:2282–2291PubMedGoogle Scholar
  84. Johnson-Leger C, Christensen J, Klaus GG (1998) CD28 co-stimulation stabilizes the expression of the CD40 ligand on T cells. Int Immunol 10:1083–1091PubMedGoogle Scholar
  85. Jumper MD, Splawski JB, Lipsky PE et al (1994) Ligation of CD40 induces sterile transcripts of multiple Ig H chain isotypes in human B cells. J Immunol 152:438–445PubMedGoogle Scholar
  86. Jumper MD, Nishioka Y, Davis LS et al (1995) Regulation of human B cell function by recombinant CD40 ligand and other TNF-related ligands. J Immunol 155:2369–2378PubMedGoogle Scholar
  87. Jung D, Néron S, Drouin M et al (2005) Efficient gene transfer into normal human B lymphocytes with the chimeric adenoviral vector Ad5/F35. J Immunol Methods 304:78–87PubMedGoogle Scholar
  88. Kaminski DA, Lee BO, Eaton SM et al (2009) CD28 and inducible costimulator (ICOS) signalling can sustain CD154 expression on activated T cells. Immunology 127:373–385PubMedGoogle Scholar
  89. Kater AP, Evers LM, Remmerswaal EB et al (2004) CD40 stimulation of B-cell chronic lymphocytic leukaemia cells enhances the anti-apoptotic profile, but also Bid expression and cells remain susceptible to autologous cytotoxic T-lymphocyte attack. Br J Haematol 127:404–415PubMedGoogle Scholar
  90. Kato K, Santana-Sahagun E, Rassenti LZ et al (1999) The soluble CD40 ligand sCD154 in systemic lupus erythematosus. J Clin Invest 104:947–955PubMedGoogle Scholar
  91. Kehry MR, Castle BE (1994) Regulation of CD40 ligand expression and use of recombinant CD40 ligand for studying B cell growth and differentiation. Semin Immunol 6:287–294PubMedGoogle Scholar
  92. Kehry MR, Hodgkin PD (1994) B-cell activation by helper T-cell membranes. Crit Rev Immunol 14:221–238PubMedGoogle Scholar
  93. Kilinc MO, Mukundan L, Yolcu ES et al (2006) Generation of a multimeric form of CD40L with potent immunostimulatory activity using streptavidin as a chaperon. Exp Mol Pathol 80:252–261PubMedGoogle Scholar
  94. Kilmon MA, Wagner NJ, Garland AL et al (2007) Macrophages prevent the differentiation of autoreactive B cells by secreting CD40 ligand and interleukin-6. Blood 110:1595–1602PubMedGoogle Scholar
  95. Klaus SJ, Berberich I, Shu G et al (1994) CD40 and its ligand in the regulation of humoral immunity. Semin Immunol 6:279–286PubMedGoogle Scholar
  96. Kobayashi N, Nagumo H, Agematsu K (2002) IL-10 enhances B-cell IgE synthesis by promoting differentiation into plasma cells, a process that is inhibited by CD27/CD70 interaction. Clin Exp Immunol 129:446–452PubMedGoogle Scholar
  97. Koguchi Y, Thauland TJ, Slifka MK et al (2007) Preformed CD40 ligand exists in secretory lysosomes in effector and memory CD4+ T cells and is quickly expressed on the cell surface in an antigen-specific manner. Blood 110:2520–2527PubMedGoogle Scholar
  98. Kondo E, Gryschok L, Klein-Gonzalez N et al (2009a) CD40-activated B cells can be generated in high number and purity in cancer patients: analysis of immunogenicity and homing potential. Clin Exp Immunol 155:249–256PubMedGoogle Scholar
  99. Kondo E, Gryschok L, Schultze JL et al (2009b) Using CD40-activated B Cells to efficiently identify epitopes of tumor antigens. J Immunother 32:157–160PubMedGoogle Scholar
  100. Koshy M, Berger D, Crow MK (1996) Increased expression of CD40 ligand on systemic lupus erythematosus lymphocytes. J Clin Invest 98:826–837PubMedGoogle Scholar
  101. Lane P, Brocker T, Hubele S et al (1993) Soluble CD40 ligand can replace the normal T cell-derived CD40 ligand signal to B cells in T cell-dependent activation. J Exp Med 177:1209–1213PubMedGoogle Scholar
  102. Lane P, Burdet C, McConnell F et al (1995) CD40 ligand-independent B cell activation revealed by CD40 ligand-deficient T cell clones: evidence for distinct activation requirements for antibody formation and B cell proliferation. Eur J Immunol 25:1788–1793PubMedGoogle Scholar
  103. Lapointe R, Lemieux R, Olivier M et al (1996) Tyrosine kinase and cAMP-dependent protein kinase activities in CD40-activated human B lymphocytes. Eur J Immunol 26:2376–2382PubMedGoogle Scholar
  104. Lapointe R, Bellemare-Pelletier A, Housseau F et al (2003) CD40-stimulated B lymphocytes pulsed with tumor antigens are effective antigen-presenting cells that can generate specific T cells. Cancer Res 63:2836–2843PubMedGoogle Scholar
  105. Ledbetter JA, Grosmaire LS, Hollenbaugh D et al (1994) Agonistic and antagonistic properties of CD40 mAb G28-5 are dependent on binding valency. Circ Shock 44:67–72PubMedGoogle Scholar
  106. Lee BO, Haynes L, Eaton SM et al (2002) The biological outcome of CD40 signaling is dependent on the duration of CD40 ligand expression: reciprocal regulation by interleukin (IL)-4 and IL-12. J Exp Med 196:693–704PubMedGoogle Scholar
  107. Lesley R, Kelly LM, Xu Y et al (2006) Naive CD4 T cells constitutively express CD40L and augment autoreactive B cell survival. Proc Natl Acad Sci USA 103:10717–10722PubMedGoogle Scholar
  108. Li N (2008) Platelet–lymphocyte cross-talk. J Leukoc Biol 83:1069–1078PubMedGoogle Scholar
  109. Loembe MM, Lamoureux J, Deslauriers N et al (2001) Lack of CD40-dependent B-cell proliferation in B lymphocytes isolated from patients with persistent polyclonal B-cell lymphocytosis. Br J Haematol 113:699–705PubMedGoogle Scholar
  110. Loskog AS, Eliopoulos AG (2009) The Janus faces of CD40 in cancer. Semin Immunol 21:301–307PubMedGoogle Scholar
  111. Luft T, Maraskovsky E, Schnurr M et al (2004) Tuning the volume of the immune response: strength and persistence of stimulation determine migration and cytokine secretion of dendritic cells. Blood 104:1066–1074PubMedGoogle Scholar
  112. Ma DY, Clark EA (2009) The role of CD40 and CD154/CD40L in dendritic cells. Semin Immunol 21:265–272PubMedGoogle Scholar
  113. MacDonald KP, Nishioka Y, Lipsky PE et al (1997) Functional CD40 ligand is expressed by T cells in rheumatoid arthritis. J Clin Invest 100:2404–2414PubMedGoogle Scholar
  114. Malisan F, Briere F, Bridon JM et al (1996) Interleukin-10 induces immunoglobulin G isotype switch recombination in human CD40-activated naive B lymphocytes. J Exp Med 183:937–947PubMedGoogle Scholar
  115. Malmborg Hager AC, Ellmark P, Borrebaeck CA et al (2003) Affinity and epitope profiling of mouse anti-CD40 monoclonal antibodies. Scand J Immunol 57:517–524PubMedGoogle Scholar
  116. Mathur RK, Awasthi A, Wadhone P et al (2004) Reciprocal CD40 signals through p38MAPK and ERK-1/2 induce counteracting immune responses. Nat Med 10:540–544PubMedGoogle Scholar
  117. Mazzei GJ, Edgerton MD, Losberger C et al (1995) Recombinant soluble trimeric CD40 ligand is biologically active. J Biol Chem 270:7025–7028PubMedGoogle Scholar
  118. McDyer JF, Li Z, John S et al (2002) IL-2 receptor blockade inhibits late, but not early, IFN-gamma and CD40 ligand expression in human T cells: disruption of both IL-12-dependent and -independent pathways of IFN-gamma production. J Immunol 169:2736–2746PubMedGoogle Scholar
  119. Miyashita T, McIlraith MJ, Grammer AC et al (1997) Bidirectional regulation of human B cell responses by CD40–CD40 ligand interactions. J Immunol 158:4620–4633PubMedGoogle Scholar
  120. Monks CR, Freiberg BA, Kupfer H et al (1998) Three-dimensional segregation of supramolecular activation clusters in T cells. Nature 395:82–86PubMedGoogle Scholar
  121. Morris AE, Remmele RL Jr, Klinke R et al (1999) Incorporation of an isoleucine zipper motif enhances the biological activity of soluble CD40L (CD154). J Biol Chem 274:418–423PubMedGoogle Scholar
  122. Munroe ME (2009) Functional roles for T cell CD40 in infection and autoimmune disease: the role of CD40 in lymphocyte homeostasis. Semin Immunol 21:283–288PubMedGoogle Scholar
  123. Nagumo H, Agematsu K, Shinozaki K et al (1998) CD27/CD70 interaction augments IgE secretion by promoting the differentiation of memory B cells into plasma cells. J Immunol 161:6496–6502PubMedGoogle Scholar
  124. Nagumo H, Agematsu K, Kobayashi N et al (2002) The different process of class switching and somatic hypermutation; a novel analysis by (CD27-) naïve B cells. Blood 99:567–575PubMedGoogle Scholar
  125. Néron S, Pelletier A, Chevrier MC et al (1996) Induction of LFA-1 independent human B cell proliferation and differentiation by binding of CD40 with its ligand. Immunol Invest 25:79–89PubMedGoogle Scholar
  126. Néron S, Racine C, Roy A et al (2005) Differential responses of human B-lymphocyte subpopulations to graded levels of CD40–CD154 interaction. Immunology 116:454–463PubMedGoogle Scholar
  127. Néron S, Suck G, Ma XZ et al (2006) B cell proliferation following CD40 stimulation results in the expression and activation of Src protein tyrosine kinase. Int Immunol 18:375–387PubMedGoogle Scholar
  128. Noelle RJ, Roy M, Shepherd DM et al (1992) A 39-kDa protein on activated helper T cells binds CD40 and transduces the signal for cognate activation of B cells. Proc Natl Acad Sci USA 89:6550–6554PubMedGoogle Scholar
  129. Nolte MA, van Olffen RW, van Gisbergen K et al (2009) Timing and tuning of CD27–CD70 interactions: the impact of signal strength in setting the balance between adaptive responses and immunopathology. Immunol Rev 229:216–231PubMedGoogle Scholar
  130. Park JY, Yoon SH, Kim EK et al (2008) A membrane-bound form of IL-4 enhances proliferation and antigen presentation of CD40-activated human B cells. Immunol Lett 116:33–40PubMedGoogle Scholar
  131. Paulie S, Ehlin-Henriksson B, Mellstedt H et al (1985) A p50 surface antigen restricted to human urinary bladder carcinomas and B lymphocytes. Cancer Immunol Immunother 20:23–28PubMedGoogle Scholar
  132. Paulie S, Rosen A, Ehlin-Henriksson B et al (1989) The human B lymphocyte and carcinoma antigen, CDw40, is a phosphoprotein involved in growth signal transduction. J Immunol 142:590–595PubMedGoogle Scholar
  133. Peltz GA, Trounstine ML, Moore KW (1988) Cloned and expressed human Fc receptor for IgG mediates anti-CD3-dependent lymphoproliferation. J Immunol 141:1891–1896PubMedGoogle Scholar
  134. Peng X, Remacle JE, Kasran A et al (1998) IL-12 up-regulates CD40 ligand (CD154) expression on human T cells. J Immunol 160:1166–1172PubMedGoogle Scholar
  135. Peters AL, Stunz LL, Bishop GA (2009) CD40 and autoimmunity: the dark side of a great activator. Semin Immunol 21:293–300PubMedGoogle Scholar
  136. Pietravalle F, Lecoanet-Henchoz S, Blasey H et al (1996) Human native soluble CD40L is a biologically active trimer, processed inside microsomes. J Biol Chem 271:5965–5967PubMedGoogle Scholar
  137. Pound JD, Challa A, Holder MJ et al (1999) Minimal cross-linking and epitope requirements for CD40-dependent suppression of apoptosis contrast with those for promotion of the cell cycle and homotypic adhesions in human B cells. Int Immunol 11:11–20PubMedGoogle Scholar
  138. Prahalad S, Martins TB, Tebo AE et al (2008) Elevated serum levels of soluble CD154 in children with juvenile idiopathic arthritis. Pediatr Rheumatol Online J 6:8PubMedGoogle Scholar
  139. Pullen SS, Miller HG, Everdeen DS et al (1998) CD40-tumor necrosis factor receptor-associated factor (TRAF) interactions: regulation of CD40 signaling through multiple TRAF binding sites and TRAF hetero-oligomerization. Biochemistry 37:11836–11845PubMedGoogle Scholar
  140. Pullen SS, Dang TT, Crute JJ et al (1999) CD40 signaling through tumor necrosis factor receptor-associated factors (TRAFs). Binding site specificity and activation of downstream pathways by distinct TRAFs. J Biol Chem 274:14246–14254PubMedGoogle Scholar
  141. Quezada SA, Jarvinen LZ, Lind EF et al (2004) CD40/CD154 interactions at the interface of tolerance and immunity. Annu Rev Immunol 22:307–328PubMedGoogle Scholar
  142. Randall TD, Heath AW, Santos-Argumedo L et al (1998) Arrest of B lymphocyte terminal differentiation by CD40 signaling: mechanism for lack of antibody-secreting cells in germinal centers. Immunity 8:733–742PubMedGoogle Scholar
  143. Ren CL, Morio T, Fu SM et al (1994) Signal transduction via CD40 involves activation of lyn kinase and phosphatidylinositol-3-kinase, and phosphorylation of phospholipase C gamma 2. J Exp Med 179:673–680PubMedGoogle Scholar
  144. Riol-Blanco L, Delgado-Martin C, Sanchez-Sanchez N et al (2009) Immunological synapse formation inhibits, via NF-kappaB and FOXO1, the apoptosis of dendritic cells. Nat Immunol 10:753–760PubMedGoogle Scholar
  145. Rizvi M, Pathak D, Freedman JE et al (2008) CD40–CD40 ligand interactions in oxidative stress, inflammation and vascular disease. Trends Mol Med 14:530–538PubMedGoogle Scholar
  146. Rousset F, Garcia E, Banchereau J (1991) Cytokine-induced proliferation and immunoglobulin production of human B lymphocytes triggered through their CD40 antigen. J Exp Med 173:705–710PubMedGoogle Scholar
  147. Rousset F, Peyrol S, Garcia E et al (1995) Long-term cultured CD40-activated B lymphocytes differentiate into plasma cells in response to IL-10 but not IL-4. Int Immunol 7:1243–1253PubMedGoogle Scholar
  148. Roy M, Waldschmidt T, Aruffo A et al (1993) The regulation of the expression of gp39, the CD40 ligand, on normal and cloned CD4+ T cells. J Immunol 151:2497–2510PubMedGoogle Scholar
  149. Sakata N, Hamelmann E, Siadak AW et al (2000) Differential regulation of CD40-mediated human B cell responses by antibodies directed against different CD40 epitopes. Cell Immunol 201:109–123PubMedGoogle Scholar
  150. Schultze JL, Cardoso AA, Freeman GJ et al (1995) Follicular lymphomas can be induced to present alloantigen efficiently: a conceptual model to improve their tumor immunogenicity. Proc Natl Acad Sci USA 92:8200–8204PubMedGoogle Scholar
  151. Schultze JL, Michalak S, Seamon MJ et al (1997) CD40-activated human B cells: an alternative source of highly efficient antigen presenting cells to generate autologous antigen-specific T cells for adoptive immunotherapy. J Clin Invest 100:2757–2765PubMedGoogle Scholar
  152. Sipsas NV, Sfikakis PP, Kontos A et al (2002) Levels of soluble CD40 ligand (CD154) in serum are increased in human immunodeficiency virus type 1-infected patients and correlate with CD4(+) T-cell counts. Clin Diagn Lab Immunol 9:558–561PubMedGoogle Scholar
  153. Skov S, Bonyhadi M, Odum N et al (2000) IL-2 and IL-15 regulate CD154 expression on activated CD4 T cells. J Immunol 164:3500–3505PubMedGoogle Scholar
  154. Snyder JT, Shen J, Azmi H et al (2007) Direct inhibition of CD40L expression can contribute to the clinical efficacy of daclizumab independently of its effects on cell division and Th1/Th2 cytokine production. Blood 109:5399–5406PubMedGoogle Scholar
  155. Sowa JM, Crist SA, Ratliff TL et al (2009) Platelet influence on T- and B-cell responses. Arch Immunol Ther Exp 57:235–241Google Scholar
  156. Splawski JB, Fu SM, Lipsky PE (1993) Immunoregulatory role of CD40 in human B cell differentiation. J Immunol 150:1276–1285PubMedGoogle Scholar
  157. Spriggs MK, Armitage RJ, Strockbine L et al (1992) Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion. J Exp Med 176:1543–1550PubMedGoogle Scholar
  158. Stewart R, Wei W, Challa A et al (2007) CD154 tone sets the signaling pathways and transcriptome generated in model CD40-pluricompetent L3055 Burkitt’s lymphoma cells. J Immunol 179:2705–2712PubMedGoogle Scholar
  159. Subauste CS, Wessendarp M, Sorensen RU et al (1999) CD40–CD40 ligand interaction is central to cell-mediated immunity against Toxoplasma gondii: patients with hyper IgM syndrome have a defective type 1 immune response that can be restored by soluble CD40 ligand trimer. J Immunol 162:6690–6700PubMedGoogle Scholar
  160. Tamura N, Kobayashi S, Kato K et al (2001) Soluble CD154 in rheumatoid arthritis: elevated plasma levels in cases with vasculitis. J Rheumatol 28:2583–2590PubMedGoogle Scholar
  161. Tangye SG, Good KL (2007) Human IgM+CD27+ B cells: memory B cells or “memory” B cells? J Immunol 179:13–19PubMedGoogle Scholar
  162. Tangye SG, Liu YJ, Aversa G et al (1998) Identification of functional human splenic memory B cells by expression of CD148 and CD27. J Exp Med 188:1691–1703PubMedGoogle Scholar
  163. Tangye SG, Ferguson A, Avery DT et al (2002a) Isotype switching by human B cells is division-associated and regulated by cytokines. J Immunol 169:4298–4306PubMedGoogle Scholar
  164. Tangye SG, van de Weerdt BC, Avery DT et al (2002b) CD84 is up-regulated on a major population of human memory B cells and recruits the SH2 domain containing proteins SAP and EAT-2. Eur J Immunol 32:1640–1649PubMedGoogle Scholar
  165. Tangye SG, Avery DT, Deenick EK et al (2003a) Intrinsic differences in the proliferation of naïve and memory human B cells as a mechanism for enhanced secondary immune responses. J Immunol 170:686–694PubMedGoogle Scholar
  166. Tangye SG, Avery DT, Hodgkin PD (2003b) A division-linked mechanism for the rapid generation of Ig-secreting cells from human memory B cells. J Immunol 170:261–269PubMedGoogle Scholar
  167. Toubi E, Shoenfeld Y (2004) The role of CD40–CD154 interactions in autoimmunity and the benefit of disrupting this pathway. Autoimmunity 37:457–464PubMedGoogle Scholar
  168. Tu W, Lau YL, Zheng J et al (2008) Efficient generation of human alloantigen-specific CD4+ regulatory T cells from naive precursors by CD40-activated B cells. Blood 112:2554–2562PubMedGoogle Scholar
  169. Unternaehrer JJ, Chow A, Pypaert M et al (2007) The tetraspanin CD9 mediates lateral association of MHC class II molecules on the dendritic cell surface. Proc Natl Acad Sci USA 104:234–239PubMedGoogle Scholar
  170. Urashima M, Chauhan D, Uchiyama H et al (1995) CD40 ligand triggered interleukin-6 secretion in multiple myeloma. Blood 85:1903–1912PubMedGoogle Scholar
  171. Urquizu-Padilla M, Balada E, Cortes F et al (2009) Serum levels of soluble CD40 ligand at flare and at remission in patients with systemic lupus erythematosus. J Rheumatol 36:953–960PubMedGoogle Scholar
  172. Valle A, Zuber CE, Defrance T et al (1989) Activation of human B lymphocytes through CD40 and interleukin 4. Eur J Immunol 19:1463–1467PubMedGoogle Scholar
  173. Van Kooten C, Banchereau J (1996) CD40–CD40 ligand: a multifunctional receptor–ligand pair. Adv Immunol 61:1–77PubMedGoogle Scholar
  174. Van Kooten C, Banchereau J (2000) CD40–CD40 ligand. J Leukoc Biol 67:2–17PubMedGoogle Scholar
  175. von Bergwelt-Baildon M, Vonderheide RH, Maecker B et al (2002) Human primary and memory cytotoxic T lymphocyte responses are efficiently induced by means of CD40-activated B cells as antigen-presenting cells: potential for clinical application. Blood 99:3319–3325Google Scholar
  176. von Bergwelt-Baildon M, Schultze JL, Maecker B et al (2004) Correspondence re R. Lapointe et al., CD40-stimulated B lymphocytes pulsed with tumor antigens are effective antigen-presenting cells that can generate specific T cells. Cancer Res 64:4055–4056Google Scholar
  177. von Bergwelt-Baildon M, Shimabukuro-Vornhagen A, Popov A et al (2006) CD40-activated B cells express full lymph node homing triad and induce T-cell chemotaxis: potential as cellular adjuvants. Blood 107:2786–2789Google Scholar
  178. Wetzel SA, McKeithan TW, Parker DC (2002) Live-cell dynamics and the role of costimulation in immunological synapse formation. J Immunol 169:6092–6101PubMedGoogle Scholar
  179. Wiesner M, Zentz C, Mayr C et al (2008) Conditional immortalization of human B cells by CD40 ligation. PLoS One 3:e1464PubMedGoogle Scholar
  180. Yellin MJ, Sippel K, Inghirami G et al (1994) CD40 molecules induce down-modulation and endocytosis of T cell surface T cell-B cell activating molecule/CD40-L. Potential role in regulating helper effector function. J Immunol 152:598–608PubMedGoogle Scholar
  181. Yi Y, McNerney M, Datta SK (2000) Regulatory defects in Cbl and mitogen-activated protein kinase (extracellular signal-related kinase) pathways cause persistent hyperexpression of CD40 ligand in human lupus T cells. J Immunol 165:6627–6634PubMedGoogle Scholar
  182. Younes A, Snell V, Consoli U et al (1998) Elevated levels of biologically active soluble CD40 ligand in the serum of patients with chronic lymphocytic leukaemia. Br J Haematol 100:135–141PubMedGoogle Scholar
  183. Yuseff MI, Lankar D, Lennon-Dumenil AM (2009) Dynamics of membrane trafficking downstream of B and T cell receptor engagement: impact on immune synapses. Traffic 10:629–636PubMedGoogle Scholar
  184. Zheng J, Liu Y, Qin G et al (2009) Efficient induction and expansion of human alloantigen-specific CD8 regulatory T cells from naive precursors by CD40-activated B cells. J Immunol 183:3742–3750PubMedGoogle Scholar
  185. Zheng J, Liu Y, Lau YL et al (2010) CD40-activated B cells are more potent than immature dendritic cells to induce and expand CD4(+) regulatory T cells. Cell Mol Immunol 7:44–50PubMedGoogle Scholar

Copyright information

© L. Hirszfeld Institute of Immunology and Experimental Therapy, Wroclaw, Poland 2011

Authors and Affiliations

  • Sonia Néron
    • 1
    • 2
    Email author
  • Philippe J. Nadeau
    • 1
  • André Darveau
    • 2
  • Jean-François Leblanc
    • 1
  1. 1.Ingénierie cellulaire, Recherche et développementHéma-QuébecQuébecCanada
  2. 2.Département de biochimie et microbiologie, Faculté des sciences et de génieUniversité LavalQuébecCanada

Personalised recommendations