Skip to main content
NCBI home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1994 Jul 1;180(1):141–155. doi: 10.1084/jem.180.1.141

Memory B cell development but not germinal center formation is impaired by in vivo blockade of CD40-CD40 ligand interaction

PMCID: PMC2191540  PMID: 7516404

Abstract

To study the role of the CD40-CD40 ligand interaction in the development of memory B cells and its level of action during primary antibody responses in vivo, mice were injected with a soluble CD40 fusion protein (sCD40-gamma 1), so as to block the interaction. The effects of the treatment on the primary antibody response were reminiscent of hyper-immunoglobulin M (IgM) syndrome (HIMG1): antigen- specific IgG responses were grossly inhibited whereas the IgM response was augmented severalfold. The latter observation suggests that there is a T-dependent, CD40 ligand-independent pathway of B cell activation that leads to IgM responses and that a significant component of the IgM in HIMG1 patients is derived from T-dependent responses. The secondary response was not readily blocked by sCD40-gamma 1 treatment, indicating a relative independence of CD40 ligation of antigen-experienced B cells. The most striking finding from these studies is that the development of memory B cell populations (measured by adoptive transfer) is grossly impaired by administration of sCD40-gamma 1 during the early induction phase of the response. It is surprising that although the generation memory is diminished, there is no quantitative difference in the development of germinal centers. Whereas entry of B cells into the memory cell pathway is dependent on CD40 ligation, the clonal expansion of the potential memory precursors in germinal centers seems not to require a CD40 signal.

Full Text

The Full Text of this article is available as a PDF (2.4 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aruffo A., Farrington M., Hollenbaugh D., Li X., Milatovich A., Nonoyama S., Bajorath J., Grosmaire L. S., Stenkamp R., Neubauer M. The CD40 ligand, gp39, is defective in activated T cells from patients with X-linked hyper-IgM syndrome. Cell. 1993 Jan 29;72(2):291–300. doi: 10.1016/0092-8674(93)90668-g. [DOI] [PubMed] [Google Scholar]
  2. Berek C., Berger A., Apel M. Maturation of the immune response in germinal centers. Cell. 1991 Dec 20;67(6):1121–1129. doi: 10.1016/0092-8674(91)90289-b. [DOI] [PubMed] [Google Scholar]
  3. Brian A. A. Stimulation of B-cell proliferation by membrane-associated molecules from activated T cells. Proc Natl Acad Sci U S A. 1988 Jan;85(2):564–568. doi: 10.1073/pnas.85.2.564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Camerini D., Walz G., Loenen W. A., Borst J., Seed B. The T cell activation antigen CD27 is a member of the nerve growth factor/tumor necrosis factor receptor gene family. J Immunol. 1991 Nov 1;147(9):3165–3169. [PubMed] [Google Scholar]
  5. Coffman R. L., Lebman D. A., Rothman P. Mechanism and regulation of immunoglobulin isotype switching. Adv Immunol. 1993;54:229–270. doi: 10.1016/s0065-2776(08)60536-2. [DOI] [PubMed] [Google Scholar]
  6. DiSanto J. P., Bonnefoy J. Y., Gauchat J. F., Fischer A., de Saint Basile G. CD40 ligand mutations in x-linked immunodeficiency with hyper-IgM. Nature. 1993 Feb 11;361(6412):541–543. doi: 10.1038/361541a0. [DOI] [PubMed] [Google Scholar]
  7. Dürkop H., Latza U., Hummel M., Eitelbach F., Seed B., Stein H. Molecular cloning and expression of a new member of the nerve growth factor receptor family that is characteristic for Hodgkin's disease. Cell. 1992 Feb 7;68(3):421–427. doi: 10.1016/0092-8674(92)90180-k. [DOI] [PubMed] [Google Scholar]
  8. Erb P., Grogg D., Troxler M., Kennedy M., Fluri M. CD4+ T cell-mediated killing of MHC class II-positive antigen-presenting cells. I. Characterization of target cell recognition by in vivo or in vitro activated CD4+ killer T cells. J Immunol. 1990 Feb 1;144(3):790–795. [PubMed] [Google Scholar]
  9. Fanslow W. C., Anderson D. M., Grabstein K. H., Clark E. A., Cosman D., Armitage R. J. Soluble forms of CD40 inhibit biologic responses of human B cells. J Immunol. 1992 Jul 15;149(2):655–660. [PubMed] [Google Scholar]
  10. Foy T. M., Laman J. D., Ledbetter J. A., Aruffo A., Claassen E., Noelle R. J. gp39-CD40 interactions are essential for germinal center formation and the development of B cell memory. J Exp Med. 1994 Jul 1;180(1):157–163. doi: 10.1084/jem.180.1.157. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Foy T. M., Shepherd D. M., Durie F. H., Aruffo A., Ledbetter J. A., Noelle R. J. 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. 1993 Nov 1;178(5):1567–1575. doi: 10.1084/jem.178.5.1567. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fuleihan R., Ramesh N., Loh R., Jabara H., Rosen R. S., Chatila T., Fu S. M., Stamenkovic I., Geha R. S. Defective expression of the CD40 ligand in X chromosome-linked immunoglobulin deficiency with normal or elevated IgM. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2170–2173. doi: 10.1073/pnas.90.6.2170. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Förster I., Rajewsky K. Expansion and functional activity of Ly-1+ B cells upon transfer of peritoneal cells into allotype-congenic, newborn mice. Eur J Immunol. 1987 Apr;17(4):521–528. doi: 10.1002/eji.1830170414. [DOI] [PubMed] [Google Scholar]
  14. Galy A. H., Spits H. CD40 is functionally expressed on human thymic epithelial cells. J Immunol. 1992 Aug 1;149(3):775–782. [PubMed] [Google Scholar]
  15. Geha R. S., Hyslop N., Alami S., Farah F., Schneeberger E. E., Rosen F. S. Hyper immunoglobulin M immunodeficiency. (Dysgammaglobulinemia). Presence of immunoglobulin M-secreting plasmacytoid cells in peripheral blood and failure of immunoglobulin M-immunoglobulin G switch in B-cell differentiation. J Clin Invest. 1979 Aug;64(2):385–391. doi: 10.1172/JCI109473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Gordon J., Millsum M. J., Flores-Romo L., Gillis S. Regulation of resting and cycling human B lymphocytes via surface IgM and the accessory molecules interleukin-4, CD23 and CD40. Immunology. 1989 Dec;68(4):526–531. [PMC free article] [PubMed] [Google Scholar]
  17. Gordon J., Millsum M. J., Guy G. R., Ledbetter J. A. Synergistic interaction between interleukin 4 and anti-Bp50 (CDw40) revealed in a novel B cell restimulation assay. Eur J Immunol. 1987 Oct;17(10):1535–1538. doi: 10.1002/eji.1830171026. [DOI] [PubMed] [Google Scholar]
  18. Grabstein K. H., Maliszewski C. R., Shanebeck K., Sato T. A., Spriggs M. K., Fanslow W. C., Armitage R. J. The regulation of T cell-dependent antibody formation in vitro by CD40 ligand and IL-2. J Immunol. 1993 Apr 15;150(8 Pt 1):3141–3147. [PubMed] [Google Scholar]
  19. Gray D. Immunological memory. Annu Rev Immunol. 1993;11:49–77. doi: 10.1146/annurev.iy.11.040193.000405. [DOI] [PubMed] [Google Scholar]
  20. Gray D., MacLennan I. C., Lane P. J. Virgin B cell recruitment and the lifespan of memory clones during antibody responses to 2,4-dinitrophenyl-hemocyanin. Eur J Immunol. 1986 Jun;16(6):641–648. doi: 10.1002/eji.1830160609. [DOI] [PubMed] [Google Scholar]
  21. Gronowicz E. S., Doss C., Schröder J. Activation to IgG secretion by lipopolysaccharide requires several proliferation cycles. J Immunol. 1979 Nov;123(5):2057–2062. [PubMed] [Google Scholar]
  22. Hodgkin P. D., Yamashita L. C., Coffman R. L., Kehry M. R. Separation of events mediating B cell proliferation and Ig production by using T cell membranes and lymphokines. J Immunol. 1990 Oct 1;145(7):2025–2034. [PubMed] [Google Scholar]
  23. Hollenbaugh D., Grosmaire L. S., Kullas C. D., Chalupny N. J., Braesch-Andersen S., Noelle R. J., Stamenkovic I., Ledbetter J. A., Aruffo A. 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. 1992 Dec;11(12):4313–4321. doi: 10.1002/j.1460-2075.1992.tb05530.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Itoh N., Yonehara S., Ishii A., Yonehara M., Mizushima S., Sameshima M., Hase A., Seto Y., Nagata S. The polypeptide encoded by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell. 1991 Jul 26;66(2):233–243. doi: 10.1016/0092-8674(91)90614-5. [DOI] [PubMed] [Google Scholar]
  25. Jacob J., Kassir R., Kelsoe G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. I. The architecture and dynamics of responding cell populations. J Exp Med. 1991 May 1;173(5):1165–1175. doi: 10.1084/jem.173.5.1165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Jacob J., Kelsoe G., Rajewsky K., Weiss U. Intraclonal generation of antibody mutants in germinal centres. Nature. 1991 Dec 5;354(6352):389–392. doi: 10.1038/354389a0. [DOI] [PubMed] [Google Scholar]
  27. Korthäuer U., Graf D., Mages H. W., Brière F., Padayachee M., Malcolm S., Ugazio A. G., Notarangelo L. D., Levinsky R. J., Kroczek R. A. Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature. 1993 Feb 11;361(6412):539–541. doi: 10.1038/361539a0. [DOI] [PubMed] [Google Scholar]
  28. Kumararatne D. S., Bazin H., MacLennan I. C. Marginal zones: the major B cell compartment of rat spleens. Eur J Immunol. 1981 Nov;11(11):858–864. doi: 10.1002/eji.1830111103. [DOI] [PubMed] [Google Scholar]
  29. Lane P., Traunecker A., Hubele S., Inui S., Lanzavecchia A., Gray D. Activated human T cells express a ligand for the human B cell-associated antigen CD40 which participates in T cell-dependent activation of B lymphocytes. Eur J Immunol. 1992 Oct;22(10):2573–2578. doi: 10.1002/eji.1830221016. [DOI] [PubMed] [Google Scholar]
  30. Levitt D., Haber P., Rich K., Cooper M. D. Hyper IgM immunodeficiency. A primary dysfunction of B lymphocyte isotype switching. J Clin Invest. 1983 Nov;72(5):1650–1657. doi: 10.1172/JCI111124. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Linton PJ L., Decker D. J., Klinman N. R. Primary antibody-forming cells and secondary B cells are generated from separate precursor cell subpopulations. Cell. 1989 Dec 22;59(6):1049–1059. doi: 10.1016/0092-8674(89)90761-7. [DOI] [PubMed] [Google Scholar]
  32. Liu Y. J., Joshua D. E., Williams G. T., Smith C. A., Gordon J., MacLennan I. C. Mechanism of antigen-driven selection in germinal centres. Nature. 1989 Dec 21;342(6252):929–931. doi: 10.1038/342929a0. [DOI] [PubMed] [Google Scholar]
  33. Liu Y. J., Mason D. Y., Johnson G. D., Abbot S., Gregory C. D., Hardie D. L., Gordon J., MacLennan I. C. Germinal center cells express bcl-2 protein after activation by signals which prevent their entry into apoptosis. Eur J Immunol. 1991 Aug;21(8):1905–1910. doi: 10.1002/eji.1830210819. [DOI] [PubMed] [Google Scholar]
  34. Mitsuya H., Tomino S., Hisamitsu S., Kishimoto S. Evidence for the failure of IgA specific T helper activity in a patient with immunodeficiency with hyper IgM. J Clin Lab Immunol. 1979 Nov;2(4):337–342. [PubMed] [Google Scholar]
  35. Nilsson U. R., Müller-Eberhard H. J. Deficiency of the fifth component of complement in mice with an inherited complement defect. J Exp Med. 1967 Jan 1;125(1):1–16. doi: 10.1084/jem.125.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Noelle R. J., Daum J., Bartlett W. C., McCann J., Shepherd D. M. Cognate interactions between helper T cells and B cells. V. Reconstitution of T helper cell function using purified plasma membranes from activated Th1 and Th2 T helper cells and lymphokines. J Immunol. 1991 Feb 15;146(4):1118–1124. [PubMed] [Google Scholar]
  37. Noelle R. J., McCann J., Marshall L., Bartlett W. C. Cognate interactions between helper T cells and B cells. III. Contact-dependent, lymphokine-independent induction of B cell cycle entry by activated helper T cells. J Immunol. 1989 Sep 15;143(6):1807–1814. [PubMed] [Google Scholar]
  38. Noelle R. J., Roy M., Shepherd D. M., Stamenkovic I., Ledbetter J. A., Aruffo A. 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 U S A. 1992 Jul 15;89(14):6550–6554. doi: 10.1073/pnas.89.14.6550. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Nonoyama S., Hollenbaugh D., Aruffo A., Ledbetter J. A., Ochs H. D. B cell activation via CD40 is required for specific antibody production by antigen-stimulated human B cells. J Exp Med. 1993 Sep 1;178(3):1097–1102. doi: 10.1084/jem.178.3.1097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Notarangelo L. D., Duse M., Ugazio A. G. Immunodeficiency with hyper-IgM (HIM). Immunodefic Rev. 1992;3(2):101–121. [PubMed] [Google Scholar]
  41. Oi V. T., Herzenberg L. A. Localization of murine Ig-1b and Ig-1a (IgG 2a) allotypic determinants detected with monoclonal antibodies. Mol Immunol. 1979 Dec;16(12):1005–1017. doi: 10.1016/0161-5890(79)90034-8. [DOI] [PubMed] [Google Scholar]
  42. Parker D. C. T cell-dependent B cell activation. Annu Rev Immunol. 1993;11:331–360. doi: 10.1146/annurev.iy.11.040193.001555. [DOI] [PubMed] [Google Scholar]
  43. Ronchese F., Hausmann B. B lymphocytes in vivo fail to prime naive T cells but can stimulate antigen-experienced T lymphocytes. J Exp Med. 1993 Mar 1;177(3):679–690. doi: 10.1084/jem.177.3.679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Rousset F., Garcia E., Banchereau J. Cytokine-induced proliferation and immunoglobulin production of human B lymphocytes triggered through their CD40 antigen. J Exp Med. 1991 Mar 1;173(3):705–710. doi: 10.1084/jem.173.3.705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Roy M., Waldschmidt T., Aruffo A., Ledbetter J. A., Noelle R. J. The regulation of the expression of gp39, the CD40 ligand, on normal and cloned CD4+ T cells. J Immunol. 1993 Sep 1;151(5):2497–2510. [PubMed] [Google Scholar]
  46. Smith C. A., Davis T., Anderson D., Solam L., Beckmann M. P., Jerzy R., Dower S. K., Cosman D., Goodwin R. G. A receptor for tumor necrosis factor defines an unusual family of cellular and viral proteins. Science. 1990 May 25;248(4958):1019–1023. doi: 10.1126/science.2160731. [DOI] [PubMed] [Google Scholar]
  47. Spriggs M. K., Armitage R. J., Strockbine L., Clifford K. N., Macduff B. M., Sato T. A., Maliszewski C. R., Fanslow W. C. Recombinant human CD40 ligand stimulates B cell proliferation and immunoglobulin E secretion. J Exp Med. 1992 Dec 1;176(6):1543–1550. doi: 10.1084/jem.176.6.1543. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Stamenkovic I., Clark E. A., Seed B. A B-lymphocyte activation molecule related to the nerve growth factor receptor and induced by cytokines in carcinomas. EMBO J. 1989 May;8(5):1403–1410. doi: 10.1002/j.1460-2075.1989.tb03521.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Tohma S., Lipsky P. E. Analysis of the mechanisms of T cell-dependent polyclonal activation of human B cells. Induction of human B cell responses by fixed activated T cells. J Immunol. 1991 Apr 15;146(8):2544–2552. [PubMed] [Google Scholar]
  50. Torres R. M., Clark E. A. Differential increase of an alternatively polyadenylated mRNA species of murine CD40 upon B lymphocyte activation. J Immunol. 1992 Jan 15;148(2):620–626. [PubMed] [Google Scholar]
  51. Vallé A., Zuber C. E., Defrance T., Djossou O., De Rie M., Banchereau J. Activation of human B lymphocytes through CD40 and interleukin 4. Eur J Immunol. 1989 Aug;19(8):1463–1467. doi: 10.1002/eji.1830190818. [DOI] [PubMed] [Google Scholar]
  52. Van den Eertwegh A. J., Noelle R. J., Roy M., Shepherd D. M., Aruffo A., Ledbetter J. A., Boersma W. J., Claassen E. In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. I. In vivo expression of CD40 ligand, cytokines, and antibody production delineates sites of cognate T-B cell interactions. J Exp Med. 1993 Nov 1;178(5):1555–1565. doi: 10.1084/jem.178.5.1555. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from The Journal of Experimental Medicine are provided here courtesy of The Rockefeller University Press

RESOURCES