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. 1996 Mar 1;183(3):979–989. doi: 10.1084/jem.183.3.979

The T cell-B cell interaction via OX40-OX40L is necessary for the T cell-dependent humoral immune response

PMCID: PMC2192367  PMID: 8642301

Abstract

Recent in vitro studies have established that activated B cells express OX40 ligand (L), a member of the tumor necrosis factor/nerve growth factor family of cytokines, and become stimulated to proliferate and secrete immunoglobulin (Ig) after cross-linking of OX40L by its counterreceptor OX40, which is expressed on activated T cells. In the present study we investigated the in vivo role of this receptor-ligand pair for the interaction of T and B cells in the course of the T- dependent B cell response against 2,4,6 trinitro-phenyl-keyhole limpet hemocyanin. First, we showed that OX40 is maximally expressed by T cells in the periarteriolar lymphoid sheath (PALS) 3 d after primary immunization. These OX40+ cells are located in close proximity to antigen-specific, activated B cells. Second, we demonstrated that blocking of OX40-OX40L interaction with polyclonal anti-OX40 antibody or with antibodies against certain peptide sequences within its extracellular domain resulted in a profound decrease of the anti-hapten IgG response, whereas the antihapten IgM response was grossly unchanged. Third, we showed that this antibody treatment leads to an inhibition of the development of PALS-associated B cell foci, whereas the formation of germinal centers remained intact. Finally, our data suggest that, whereas B cell memory development was not impaired by anti-OX40 administration, OX40-OX40L interaction seems to be crucial in the secondary immune response. We conclude from these data that the OX40-OX40L interaction in vivo is necessary for the differentiation of activated B cells into highly Ig-producing cells, but is not involved in other pathways of antigen-driven B cell differentiation such as memory cell development in the germinal centers.

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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. Allman D. M., Ferguson S. E., Lentz V. M., Cancro M. P. Peripheral B cell maturation. II. Heat-stable antigen(hi) splenic B cells are an immature developmental intermediate in the production of long-lived marrow-derived B cells. J Immunol. 1993 Nov 1;151(9):4431–4444. [PubMed] [Google Scholar]
  3. 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]
  4. Baum P. R., Gayle R. B., 3rd, Ramsdell F., Srinivasan S., Sorensen R. A., Watson M. L., Seldin M. F., Baker E., Sutherland G. R., Clifford K. N. Molecular characterization of murine and human OX40/OX40 ligand systems: identification of a human OX40 ligand as the HTLV-1-regulated protein gp34. EMBO J. 1994 Sep 1;13(17):3992–4001. doi: 10.1002/j.1460-2075.1994.tb06715.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  6. Calderhead D. M., Buhlmann J. E., van den Eertwegh A. J., Claassen E., Noelle R. J., Fell H. P. Cloning of mouse Ox40: a T cell activation marker that may mediate T-B cell interactions. J Immunol. 1993 Nov 15;151(10):5261–5271. [PubMed] [Google Scholar]
  7. Castle B. E., Kishimoto K., Stearns C., Brown M. L., Kehry M. R. Regulation of expression of the ligand for CD40 on T helper lymphocytes. J Immunol. 1993 Aug 15;151(4):1777–1788. [PubMed] [Google Scholar]
  8. Chen-Kiang S. Regulation of terminal differentiation of human B-cells by IL-6. Curr Top Microbiol Immunol. 1995;194:189–198. doi: 10.1007/978-3-642-79275-5_23. [DOI] [PubMed] [Google Scholar]
  9. Claassen E., Kors N., Van Rooijen N. Influence of carriers on the development and localization of anti-2,4,6-trinitrophenyl (TNP) antibody-forming cells in the murine spleen. II. Suppressed antibody response to TNP-Ficoll after elimination of marginal zone cells. Eur J Immunol. 1986 May;16(5):492–497. doi: 10.1002/eji.1830160505. [DOI] [PubMed] [Google Scholar]
  10. Di Santo J. P., de Saint Basile G., Durandy A., Fischer A. Hyper-IgM syndrome. Res Immunol. 1994 Mar-Apr;145(3):205–249. doi: 10.1016/s0923-2494(94)80185-1. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. 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]
  13. Fuleihan R., Ramesh N., Geha R. S. Role of CD40-CD40-ligand interaction in Ig-isotype switching. Curr Opin Immunol. 1993 Dec;5(6):963–967. doi: 10.1016/0952-7915(93)90113-7. [DOI] [PubMed] [Google Scholar]
  14. Godfrey W. R., Fagnoni F. F., Harara M. A., Buck D., Engleman E. G. Identification of a human OX-40 ligand, a costimulator of CD4+ T cells with homology to tumor necrosis factor. J Exp Med. 1994 Aug 1;180(2):757–762. doi: 10.1084/jem.180.2.757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. 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]
  16. Jacob J., Kelsoe G. In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. II. A common clonal origin for periarteriolar lymphoid sheath-associated foci and germinal centers. J Exp Med. 1992 Sep 1;176(3):679–687. doi: 10.1084/jem.176.3.679. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kelsoe G., Zheng B. Sites of B-cell activation in vivo. Curr Opin Immunol. 1993 Jun;5(3):418–422. doi: 10.1016/0952-7915(93)90062-w. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Lane P., Burdet C., Hubele S., Scheidegger D., Müller U., McConnell F., Kosco-Vilbois M. B cell function in mice transgenic for mCTLA4-H gamma 1: lack of germinal centers correlated with poor affinity maturation and class switching despite normal priming of CD4+ T cells. J Exp Med. 1994 Mar 1;179(3):819–830. doi: 10.1084/jem.179.3.819. [DOI] [PMC free article] [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. 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]
  22. Liu Y. J., Zhang J., Lane P. J., Chan E. Y., MacLennan I. C. Sites of specific B cell activation in primary and secondary responses to T cell-dependent and T cell-independent antigens. Eur J Immunol. 1991 Dec;21(12):2951–2962. doi: 10.1002/eji.1830211209. [DOI] [PubMed] [Google Scholar]
  23. MacLennan I. C. Germinal centers. Annu Rev Immunol. 1994;12:117–139. doi: 10.1146/annurev.iy.12.040194.001001. [DOI] [PubMed] [Google Scholar]
  24. Neurath M. F., Max E. E., Strober W. Pax5 (BSAP) regulates the murine immunoglobulin 3' alpha enhancer by suppressing binding of NF-alpha P, a protein that controls heavy chain transcription. Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5336–5340. doi: 10.1073/pnas.92.12.5336. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Paterson D. J., Jefferies W. A., Green J. R., Brandon M. R., Corthesy P., Puklavec M., Williams A. F. Antigens of activated rat T lymphocytes including a molecule of 50,000 Mr detected only on CD4 positive T blasts. Mol Immunol. 1987 Dec;24(12):1281–1290. doi: 10.1016/0161-5890(87)90122-2. [DOI] [PubMed] [Google Scholar]
  26. Peçanha L. M., Yamaguchi H., Lees A., Noelle R. J., Mond J. J., Snapper C. M. Dextran-conjugated anti-IgD antibodies inhibit T cell-mediated IgE production but augment the synthesis of IgM and IgG. J Immunol. 1993 Mar 15;150(6):2160–2168. [PubMed] [Google Scholar]
  27. Pulendran B., Karvelas M., Nossal G. J. A form of immunologic tolerance through impairment of germinal center development. Proc Natl Acad Sci U S A. 1994 Mar 29;91(7):2639–2643. doi: 10.1073/pnas.91.7.2639. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Ramsay A. J., Husband A. J., Ramshaw I. A., Bao S., Matthaei K. I., Koehler G., Kopf M. The role of interleukin-6 in mucosal IgA antibody responses in vivo. Science. 1994 Apr 22;264(5158):561–563. doi: 10.1126/science.8160012. [DOI] [PubMed] [Google Scholar]
  29. Ronchese F., Hausmann B., Hubele S., Lane P. Mice transgenic for a soluble form of murine CTLA-4 show enhanced expansion of antigen-specific CD4+ T cells and defective antibody production in vivo. J Exp Med. 1994 Mar 1;179(3):809–817. doi: 10.1084/jem.179.3.809. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. 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]
  31. Stüber E., Neurath M., Calderhead D., Fell H. P., Strober W. Cross-linking of OX40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells. Immunity. 1995 May;2(5):507–521. doi: 10.1016/1074-7613(95)90031-4. [DOI] [PubMed] [Google Scholar]
  32. 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]
  33. Weinstein P. D., Cebra J. J. The preference for switching to IgA expression by Peyer's patch germinal center B cells is likely due to the intrinsic influence of their microenvironment. J Immunol. 1991 Dec 15;147(12):4126–4135. [PubMed] [Google Scholar]
  34. van Kooten C., Gaillard C., Galizzi J. P., Hermann P., Fossiez F., Banchereau J., Blanchard D. B cells regulate expression of CD40 ligand on activated T cells by lowering the mRNA level and through the release of soluble CD40. Eur J Immunol. 1994 Apr;24(4):787–792. doi: 10.1002/eji.1830240402. [DOI] [PubMed] [Google Scholar]

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