CD40 Ligand Knockout Mice

  • Charles R. Maliszewski
  • Mary K. Kennedy
  • Kim A. Campbell
Part of the Contemporary Immunology book series (CONTIM)


CD40 is a 50-kDa glycoprotein expressed on B-cells, monocytes, dendritic cells, follicular dendritic cells, thymic epithelial cells, and certain carcinomas (for review, see ref. 1). Its counterstructure, CD40 ligand (CD40L), is a 33-kDa glycoprotein expressed primarily on activated CD4+ T-cells, but also found on CD8+ T-cells, mast cells, basophils (1), and eosinophils (2). CD40L belongs to the tumor necrosis factor (TNF) superfamily (3), members of which stimulate a broad range of biological functions including proliferation, induction of cytokine secretion, and apoptosis (For review, see ref. 4).


Cutaneous Leishmaniasis CD40 Ligand CD40L Expression CD40KO Mouse Cytokine Secretion Profile 
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.
    Banchereau, J., Bazan, F., Blanchard, D., Brière, F., Galizzi, J. P., van Kooten, C., Liu, Y. J., Rousset, F., and Saeland, S. (1994) The CD40 antigen and its ligand. Annu. Rev. Immunol. 12, 881–922.PubMedCrossRefGoogle Scholar
  2. 2.
    Gauchat, J.-F., Henchoz, S., Fattah, D., Mazzei, G., Aubry, J.-P., Jomotte, T., Dash, L., Page, K., Solari, R., Aldebert, D., Capron, M., Dahinden, C., and Bonnefoy, J.-Y. (1995) CD40 ligand is functionally expressed on human eosinophils. Eur. J. Immunol. 25, 863–865.PubMedCrossRefGoogle Scholar
  3. 3.
    Armitage, R. J., Fanslow, W. C., Strockbine, LL., Sato, T. A., Clifford, K. N., Macduff, B. M., Anderson, D. M., Gimpel, S. D., Davis-Smith, T., Maliszewski, C. R., Clark, E. A., Smith, C. A., Grabstein, K. H., Cosman, D., and Spriggs, M. K. (1992) Molecular and biological characterization of a murine ligand for CD40. Nature 357, 80–82.PubMedCrossRefGoogle Scholar
  4. 4.
    Alderson, M. R. (1994) Regulation of immune responses by the ligands for CD27, CD30 and 4–1BB. Circ. Shock 44, 73–76.PubMedGoogle Scholar
  5. 5.
    Noelle, R. J., Ledbetter, J. A., and Aruffo, A. (1992) CD40 and its ligand, an essential ligand-receptor pair for thymus-dependent B-cell activation. Immunol. Today 13, 431–433.PubMedCrossRefGoogle Scholar
  6. 6.
    Durie, F. H., Foy, T. M., Masters, S. R., Laman, J. D., and Noelle, R. J. (1994) The role of CD40 in the regulation of humoral and cell-mediated immunity. Immunol. Today 15, 406–411.PubMedCrossRefGoogle Scholar
  7. 7.
    Hirohata, S., Jelinek, D. F., and Lipsky, P. E. (1988) T cell-dependent activation of B cell proliferation and differentiation by immobilized monoclonal antibodies to CD3. J. Immunol. 140, 3736–3744.PubMedGoogle Scholar
  8. 8.
    Bartlett, W. C., Michael, A., McCann, J., Yuan, D., Claassen, E., and Noelle, R. J. (1989) Cognate interactions between helper T cells and B cells. II. Dissection of cognate help by using a class II-restricted, antigen-specific, IL2-dependent helper T cell clone. J. Immunol. 143, 1745–1754.PubMedGoogle Scholar
  9. 9.
    Hodgkin, P. D., Yamashita, L. C., Coffman, R. L., and Kehry, M. R. (1990) Separation of events mediating B cell proliferation and Ig production by using T cell membranes and lymphokines. J. Immunol. 145, 2025–2034.PubMedGoogle Scholar
  10. 10.
    Brian, A. A. (1988) Stimulation of B-cell proliferation by membrane-associated molecules from activated T cells. Proc. Natl. Acad. Sci. USA 85, 561 568.Google Scholar
  11. 11.
    Bartlett, W. C., McCann, J., Shepherd, D. M., Roy, M., and Noelle, R. J. (1990) Cognate interactions between helper T cells and B cells. IV. Requirements for the expression of effector phase activity by helper T cells. J. Immunol. 145, 3956–3962.PubMedGoogle Scholar
  12. 12.
    Clark, E. A. and Ledbetter, J. A. (1986) Activation of human B cells mediated through two distinct cell surface differentiation antigens, Bp35 and Bp50. Proc. Natl. Acad. Sci. USA 83, 4494–4498.PubMedCrossRefGoogle Scholar
  13. 13.
    Banchereau, J., de Paoli, P., Vallé, A., Garcia, E., and Rousset, F. (1991) Long-term human B cell lines dependent on interleukin-4 and antibody to CD40. Science 251, 70–72.PubMedCrossRefGoogle Scholar
  14. 14.
    Jabara, H. H., Fu, S. M., Geha, R. S., and Vercelli, D. (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, 1861–1864.PubMedCrossRefGoogle Scholar
  15. 15.
    Spriggs, M. K., Armitage, R. J., Strockbine, L., Clifford, K. N., Macduff, B. M., Sato, T. A., Maliszewski, C. R., and Fanslow, W. C. (1992) Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion. J. Exp. Med. 176, 1543–1550.CrossRefGoogle Scholar
  16. 16.
    Hollenbaugh, D., Grosmaire, L. S., Kullas, C. D., Chalupny, N. J., BraeschAndersen, S., Noelle, R. J., Stamenkovic, I., Ledbetter, J. A., and Aruffo, A. (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, 4313–4321.PubMedGoogle Scholar
  17. 17.
    Alderson, M. R., Armitage, R. J., Tough, T. W., Strockbine, L., Fanslow, W. C., and Spriggs, M. K. (1993) CD40 expression by human monocytes: regulation by cytokines and activation of monocytes by the ligand for CD40. J. Exp. Med. 178, 669–674.PubMedCrossRefGoogle Scholar
  18. 18.
    Wagner, D. H., Jr., Stout, R. D., and Suttles, J. (1994) Role of the CD40CD40 ligand interaction in CD4+ T cell contact-dependent activation of monocyte interleukin-1 synthesis. Eur. J. Immunol. 24, 3148–3154.PubMedCrossRefGoogle Scholar
  19. 19.
    Shu, U., Kiniwa, M., Wu, C. Y., Maliszewski, C., Vezzio, N., Hakimi, J., Gately, M., and Delespesse, G. (1995) Activated T cells induce interleukin12 production by monocytes via CD40—CD40 ligand interaction. Eur. J. Immunol. 25, 1125–1128.PubMedCrossRefGoogle Scholar
  20. 20.
    Ranheim, E. A. and Kipps, T. J. (1993) Activated T cells induce expression of B7/BB 1 on normal or leukemic B cells through a CD40-dependent signal. J. Exp. Med. 177, 925–935.PubMedCrossRefGoogle Scholar
  21. 21.
    Armitage, R. J., Maliszewski, C. R., Alderson, M. R., Grabstein, K. H., Spriggs, M. K., and Fanslow, W. C. (1993) CD40L: a multi-functional ligand. Semin. Immunol. 5, 401–412.PubMedCrossRefGoogle Scholar
  22. 22.
    Klaus, S. J., Pinchuk, L. M., Ochs, H. D., Law, C.-L., Fanslow, W. C., Armitage, R. J., and Clark, E. A. (1994) Costimulation through CD28 enhances T cell-dependent B cell activation via a CD40—CD40L interaction. J. Immunol. 152, 5643–5652.PubMedGoogle Scholar
  23. 23.
    Foy, T. M., Shepherd, D. M., Durie, F. H., Aruffo, A., Ledbetter, J. A., and Noelle, R. J. (1993) In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. II. Prolonged suppression of the humoral immune response by an antibody to the ligand for CD40, gp39. J. Exp. Med. 178, 1567–1575.PubMedCrossRefGoogle Scholar
  24. 24.
    Foy, T. M., Laman, J. D., Ledbetter, J. A., Aruffo, A., Claassen, E., and Noelle, R. J. (1994) gp39—CD40 interactions are essential for germinal center formation and the development of B cell memory. J. Exp. Med. 180, 157–163.Google Scholar
  25. 25.
    Durie, F. H., Fava, R. A., Foy, T. M., Aruffo, A., Ledbetter, J. A., and Noelle, R. J. (1993) Prevention of collagen-induced arthritis with an antibody to gp39, the ligand for CD40. Science 261, 1328–1330.PubMedCrossRefGoogle Scholar
  26. 26.
    Seki, N., Sudo, Y., Mizuhara, H., Orito, K., Imasaki, A., Ono, S., Hamaoka, T., Senoh, H., and Fujiwara, H. (1992) Type II collagen-induced murine arthritis: induction of arthritis depends on antigen-presenting cell function as well as susceptibility of host to an anticollagen immune response. J. Immunol. 148, 3093–3099.PubMedGoogle Scholar
  27. 27.
    Durie, F. H., Aruffo, A., Ledbetter, J., Crassi, K. M., Green, W. R., Fast, L. D., and Noelle, R. J. (1994) Antibody to the ligand of CD40, gp39, blocks the occurrence of the acute and chronic forms of graft-vs-host disease. J. Clin. Invest. 94, 1333–1338.PubMedCrossRefGoogle Scholar
  28. 28.
    Buhlmann, J. E., Foy, T. M., Aruffo, A., Crassi, K. M., Ledbetter, J. A., Green, W. R., Xu, J. C., Shultz, L. D., Roopesian, D., Flavell, R. A., Fast, L., Noelle, R. J., and Durie, F. H. (1995) In the absence of a CD40 signal, B cells are tolerogenic. Immunity 2, 645–653.PubMedCrossRefGoogle Scholar
  29. 29.
    Parker, D. C., Greiner, D. L., Phillips, N. E.., Appel, M. C., Steele, A. W., Durie, F. H., Noelle, R. J., Mordes, J. P., and Rossini, A. A. (1995) Survival of mouse pancreatic islet allografts in recipients treated with allogeneic small lymphocytes and antibody to CD40 ligand. Proc. Natl. Acad. Sci. USA 92, 9560–9564.PubMedCrossRefGoogle Scholar
  30. 30.
    Callard, R. E., Armitage, R. J., Fanslow, W. C., and Spriggs, M. K. (1993) CD40 ligand and its role in X-linked hyper-IgM syndrome. Immunol. Today 14, 559–564.PubMedCrossRefGoogle Scholar
  31. 31.
    Notarangelo, L. D., Duse, M., and Ugazio, A. G. (1992) Immunodeficiency with hyper-IgM (HIM). Immunodefic. Rev. 3, 101–121.PubMedGoogle Scholar
  32. 32.
    Wiley, J. A. and Harmsen, A. G. (1995) CD40 ligand is required for resolution of Pneumocystis carinii pneumonia in mice. J. Immunol. 155, 3525–3529.PubMedGoogle Scholar
  33. 33.
    Renshaw, B., Fanslow, W. C., III, Armitage, R. J., Campbell, K. A., Liggitt, D., Wright, B., Davison, B., and Maliszewski, C. R. (1994) Humoral immune responses in CD40 ligand-deficient mice. J. Exp. Med. 180, 1889–1900.PubMedCrossRefGoogle Scholar
  34. 34.
    Xu, J., Foy, T. M., Laman, J. D., Elliott, E. A., Dunn, J. J., Waldschmidt, T. J., Elsemore, J., Noelle, R. J., and Flavell, R. A. (1994) Mice deficient for the CD40 ligand. Immunity 1, 423–431.PubMedCrossRefGoogle Scholar
  35. 35.
    Kawabe, T., Naka, T., Yoshida, K., Tanaka, T., Fujiwara, H., Suematsu, S., Yoshida, N., Kishimoto, T., and Kikutani, H. (1994) The immune responses in CD40-deficient mice: impaired immunoglobulin class switching and germinal center formation. Immunity 1, 167–178.PubMedCrossRefGoogle Scholar
  36. 36.
    Kennedy, M. K., Picha, K. S., Fanslow, W. C., Grabstein, K. H., Alderson, M. R., Clifford, K. N., Chin, W. A., and Mohler, K. M. (1995) CD40/CD40 ligand interactions are required for T cell-dependent production of interleukin-12 by mouse macrophages. Eur. J. Immunol. 26, 370–378.CrossRefGoogle Scholar
  37. 37.
    Shanebeck, K. D., Maliszewski, C. R., Kennedy, M. K., Picha, K. S., Smith, C. A., Goodwin, R. G., and Grabstein, K. H. (1995) Regulation of murine B cell growth and differentiation by CD30 ligand. Eur. J. Immunol. 25, 2147–2153.PubMedCrossRefGoogle Scholar
  38. 38.
    Smith, C. A., Gruss, H.-J., Davis, T., Anderson, D., Farrah, T., Baker, E., Sutherland, G. R., Brannan, C. I., Copeland, N. G., Jenkins, N. A., Grabstein, K. H., Gliniak, B., McAlister, I. B., Fanslow, W., Alderson, M., Falk, B., Gimpel, S., Gillis, S., Din, W. S., Goodwin, R. G., and Armitage, R. J. (1993) CD30 antigen, a marker for Hodgkin’s lymphoma, is a receptor whose ligand defines an emerging family of cytokines with homology to TNF. Cell 73, 1349–1360.PubMedCrossRefGoogle Scholar
  39. 39.
    Perlmutter, R. M., Hamburg, D., Briles, D. E., Nicolotti, R. A., and Davie, J. M. (1978) Subclass restriction of murine anti-carbohydrate antibodies. J. Immunol. 121, 566–572.PubMedGoogle Scholar
  40. 40.
    Mond, J. J. and Brunswick, M. (1987) A role for IFN-y and NK cells in immune responses to T cell-regulated antigens types 1 and 2. Immunol. Rev. 99, 105–118.PubMedCrossRefGoogle Scholar
  41. 41.
    Aversa, G., Punnonen, J., and de Vries, J. E. (1993) The 26-kD transmembrane form of tumor necrosis factor a on activated CD4+ T cell clones provides a costimulatory signal for human B cell activation. J. Exp. Med. 177, 1575–1585.PubMedCrossRefGoogle Scholar
  42. 42.
    Gray, D., Dullforce, P., and Jainandunsing, S. (1994) Memory B cell development but not germinal center formation is impaired by in vivo blockade of CD40–CD40ligand interaction. J. Exp. Med. 180, 141–155.PubMedCrossRefGoogle Scholar
  43. 43.
    Gray, D., Siepmann, K., and Wohlleben, G. (1994) CD40 ligation in B cell activation, isotype switching and memory development. Semin. Immunol. 6, 303–310.PubMedCrossRefGoogle Scholar
  44. 44.
    Peçanha, L. M. T., Snapper, C. M., Finkelman, F D, and Mond, J. J. (1991) Dextran-conjugated anti-Ig antibodies as a model for T cell-independent type 2 antigen-mediated stimulation of Ig secretion in vitro. I. Lymphokine dependence. J. Immunol. 146, 833–839.PubMedGoogle Scholar
  45. 45.
    Snapper, C. M. and Mond, J. J. (1993) Towards a comprehensive view of immunoglobulin class switching. Immunol. Today 14, 15–17.PubMedCrossRefGoogle Scholar
  46. 46.
    Foy, T. M. and Waldschmidt, T. J. (1993) Switching capacity of FcERIIpositive and -negative murine B cells. Eur. J. Immunol. 23, 3208–3216.PubMedCrossRefGoogle Scholar
  47. 47.
    Haughton, G., Arnold, L. W., Whitmore, A. C., and Clarke, S. H. (1993) B-1 cells are made, not born. Immunol. Today 14, 84–87.PubMedCrossRefGoogle Scholar
  48. 48.
    Reiner, S. L. and Locksley, R. M. (1995) The regulation of immunity to Leishmania major. Annu. Rev. Immunol. 13, 151–177.CrossRefGoogle Scholar
  49. 49.
    Campbell, K. A., Ovendale, P. J., Fanslow, W. C., Reed, S. G., and Maliszewski, C. R. (1996) CD40L is required to generate a protective cell-mediated immune response to Leishmania major. Immunity 4, 283–289.CrossRefGoogle Scholar
  50. 50.
    Hsieh, C.-S., Macatonia, S. E., Tripp, C. S., Wolf, S. F., O’Garra, A., and Murphy, K. M. (1993) Development of TH1 CD4+ T cells through IL-12 produced by Listeria-induced macrophages. Science 260, 547–549.PubMedCrossRefGoogle Scholar
  51. 51.
    Seder, R. A. and Paul, W. E. (1994) Acquisition of lymphokine-producing phenotype by CD4+ T cells. Annu. Rev. Immunol. 12, 635–673.PubMedCrossRefGoogle Scholar
  52. 52.
    Trinchieri, G. (1995) Interleukin-12: a proinflammatory cytokine with immunoregulatory functions that bridge innate resistance and antigen-specific adaptive immunity. Annu. Rev. Immunol. 13, 251–276.PubMedCrossRefGoogle Scholar
  53. 53.
    Heinzel, F. P., Sadick, M. D., Holaday, B. J., Coffman, R. L., and Locksley, R. M. (1989) Reciprocal expression of interferon y or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for expansion of distinct helper T cell subsets. J. Exp. Med. 169, 59–72.PubMedCrossRefGoogle Scholar
  54. 54.
    Sypek, J. P., Chung, C. L., Mayor, S. E. H., Subramanyam, J. M., Goldman, S. J., Sieburth, D. S., Wolf, S. F., and Schaub, R. G. (1993) Resolution of cutaneous leishmaniasis: interleukin 12 initiates a protective T helper type 1 immune response. J. Exp. Med. 177, 1797–1802.PubMedCrossRefGoogle Scholar
  55. 55.
    Green, S. J., Nacy, C. A., and Meltzer, M. S. (1991) Cytokine-induced synthesis of nitrogen oxides in macrophages: a protective host response to Leishmania and other intracellular pathogens. J. Leukoc. Biol. 50, 93–103.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1998

Authors and Affiliations

  • Charles R. Maliszewski
  • Mary K. Kennedy
  • Kim A. Campbell

There are no affiliations available

Personalised recommendations