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. 1993 Nov 1;178(5):1567–1575. doi: 10.1084/jem.178.5.1567

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

PMCID: PMC2191245  PMID: 7693850

Abstract

The ligand for CD40 has been recently identified as a 39-kd protein, gp39, expressed on the surface of activated CD4+ T helper cells (Th). In vitro, soluble CD40 and anti-gp39 have been shown to block the ability of Th to activate B cells, suggesting that gp39-CD40 interactions are important to T cell-dependent B cell activation. Here it is shown that in vivo administration of anti-gp39 dramatically reduced both primary and secondary humoral immune responses to erythrocytes and soluble protein antigens without altering responses to the T-independent type II antigen, trinitrophenyl-Ficoll. Treatment of mice for 4 d with anti-gp39 inhibited the anti-sheep red blood cell (SRBC) response for at least 3 wk and inhibited the expression of all immunoglobulin isotypes in secondary responses to the protein antigen, keyhole limpet hemocyanin. To examine the direct effect of anti-gp39 on Th function, SRBC-immune Th cells from anti-gp39-treated mice were adoptively transferred and shown to be fully capable of providing help. These results suggest that anti-gp39 treatment does not cause Th deletion or anergy. Anti-gp39 may mediate its profound immunosuppressive effects on humoral immunity by blocking gp39-CD40 interactions. Moreover, these studies establish gp39-CD40 as an important receptor-ligand pair for the targeting of therapeutic antibodies to control thymus-dependent humoral responses.

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Selected References

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  1. Allen R. C., Armitage R. J., Conley M. E., Rosenblatt H., Jenkins N. A., Copeland N. G., Bedell M. A., Edelhoff S., Disteche C. M., Simoneaux D. K. CD40 ligand gene defects responsible for X-linked hyper-IgM syndrome. Science. 1993 Feb 12;259(5097):990–993. doi: 10.1126/science.7679801. [DOI] [PubMed] [Google Scholar]
  2. Armitage R. J., Fanslow W. C., Strockbine L., Sato T. A., Clifford K. N., Macduff B. M., Anderson D. M., Gimpel S. D., Davis-Smith T., Maliszewski C. R. Molecular and biological characterization of a murine ligand for CD40. Nature. 1992 May 7;357(6373):80–82. doi: 10.1038/357080a0. [DOI] [PubMed] [Google Scholar]
  3. Armitage R. J., Sato T. A., Macduff B. M., Clifford K. N., Alpert A. R., Smith C. A., Fanslow W. C. Identification of a source of biologically active CD40 ligand. Eur J Immunol. 1992 Aug;22(8):2071–2076. doi: 10.1002/eji.1830220817. [DOI] [PubMed] [Google Scholar]
  4. 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]
  5. Banchereau J., Rousset F. Growing human B lymphocytes in the CD40 system. Nature. 1991 Oct 17;353(6345):678–679. doi: 10.1038/353678a0. [DOI] [PubMed] [Google Scholar]
  6. Clark E. A., Ledbetter J. A. Activation of human B cells mediated through two distinct cell surface differentiation antigens, Bp35 and Bp50. Proc Natl Acad Sci U S A. 1986 Jun;83(12):4494–4498. doi: 10.1073/pnas.83.12.4494. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. 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]
  8. 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]
  9. 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]
  10. Hellström I., Horn D., Linsley P., Brown J. P., Brankovan V., Hellström K. E. Monoclonal mouse antibodies raised against human lung carcinoma. Cancer Res. 1986 Aug;46(8):3917–3923. [PubMed] [Google Scholar]
  11. 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]
  12. Inaba K., Steinman R. M. Protein-specific helper T-lymphocyte formation initiated by dendritic cells. Science. 1985 Aug 2;229(4712):475–479. doi: 10.1126/science.3160115. [DOI] [PubMed] [Google Scholar]
  13. Inaba K., Witmer M. D., Steinman R. M. Clustering of dendritic cells, helper T lymphocytes, and histocompatible B cells during primary antibody responses in vitro. J Exp Med. 1984 Sep 1;160(3):858–876. doi: 10.1084/jem.160.3.858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Jabara H. H., Fu S. M., Geha R. S., Vercelli D. 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. 1990 Dec 1;172(6):1861–1864. doi: 10.1084/jem.172.6.1861. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jerne N. K., Henry C., Nordin A. A., Fuji H., Koros A. M., Lefkovits I. Plaque forming cells: methodology and theory. Transplant Rev. 1974;18:130–191. doi: 10.1111/j.1600-065x.1974.tb01588.x. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Kurt-Jones E. A., Hamberg S., Ohara J., Paul W. E., Abbas A. K. Heterogeneity of helper/inducer T lymphocytes. I. Lymphokine production and lymphokine responsiveness. J Exp Med. 1987 Dec 1;166(6):1774–1787. doi: 10.1084/jem.166.6.1774. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. 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]
  19. Lenschow D. J., Zeng Y., Thistlethwaite J. R., Montag A., Brady W., Gibson M. G., Linsley P. S., Bluestone J. A. Long-term survival of xenogeneic pancreatic islet grafts induced by CTLA4lg. Science. 1992 Aug 7;257(5071):789–792. doi: 10.1126/science.1323143. [DOI] [PubMed] [Google Scholar]
  20. Linsley P. S., Wallace P. M., Johnson J., Gibson M. G., Greene J. L., Ledbetter J. A., Singh C., Tepper M. A. Immunosuppression in vivo by a soluble form of the CTLA-4 T cell activation molecule. Science. 1992 Aug 7;257(5071):792–795. doi: 10.1126/science.1496399. [DOI] [PubMed] [Google Scholar]
  21. Noelle R. J., Ledbetter J. A., Aruffo A. CD40 and its ligand, an essential ligand-receptor pair for thymus-dependent B-cell activation. Immunol Today. 1992 Nov;13(11):431–433. doi: 10.1016/0167-5699(92)90068-I. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Noelle R. J., Snow E. C. Cognate interactions between helper T cells and B cells. Immunol Today. 1990 Oct;11(10):361–368. doi: 10.1016/0167-5699(90)90142-v. [DOI] [PubMed] [Google Scholar]
  24. Notarangelo L. D., Duse M., Ugazio A. G. Immunodeficiency with hyper-IgM (HIM). Immunodefic Rev. 1992;3(2):101–121. [PubMed] [Google Scholar]
  25. Snow E. C., Noelle R. J. Thymus-dependent antigenic stimulation of hapten-specific B lymphocytes. Immunol Rev. 1987 Oct;99:173–192. doi: 10.1111/j.1600-065x.1987.tb01177.x. [DOI] [PubMed] [Google Scholar]
  26. 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]
  27. 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]
  28. Wilde D. B., Marrack P., Kappler J., Dialynas D. P., Fitch F. W. Evidence implicating L3T4 in class II MHC antigen reactivity; monoclonal antibody GK1.5 (anti-L3T4a) blocks class II MHC antigen-specific proliferation, release of lymphokines, and binding by cloned murine helper T lymphocyte lines. J Immunol. 1983 Nov;131(5):2178–2183. [PubMed] [Google Scholar]

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