Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1995 Jul 1;182(1):33–40. doi: 10.1084/jem.182.1.33

Expression of functional CD40 by vascular endothelial cells

PMCID: PMC2192103  PMID: 7540655

Abstract

The interaction between activated vascular endothelium and T cells has been shown to play an important role in the recruitment and activation of T cells at sites of inflammation. Here we report the expression of CD40 by vascular endothelial cells and its regulation by inflammatory agents. Using the soluble recombinant CD40 ligand, sgp39, we show that the interaction of CD40 with its ligand can lead to endothelial cell activation, which in turn leads to leukocyte adhesion. This adhesion is partly mediated by the expression of E-selectin. In addition to E- selectin expression, sgp39 induces the expression of intercellular adhesion molecule 1 and augments the tumor necrosis factor alpha- induced expression of vascular cell adhesion molecule 1. The effects of sgp39 on endothelial cells can be blocked with anti-gp39 monoclonal antibody (mAb), anti-CD40 mAb, or soluble CD40. Staining of tissues from healthy human skin using anti-CD40 mAb showed very weak expression of CD40 by the endothelium, while skin involved in inflammatory disease showed marked upregulation of CD40 expression. These studies suggest that interactions between cell surface proteins expressed by activated T cells with their receptors on vascular endothelium can stimulate the vasculature at sites of inflammation and may be involved in normal inflammatory responses and in inflammatory disease.

Full Text

The Full Text of this article is available as a PDF (1.4 MB).

Selected References

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

  1. Alderson M. R., Armitage R. J., Tough T. W., Strockbine L., Fanslow W. C., Spriggs M. K. CD40 expression by human monocytes: regulation by cytokines and activation of monocytes by the ligand for CD40. J Exp Med. 1993 Aug 1;178(2):669–674. doi: 10.1084/jem.178.2.669. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Armitage R. J., Tough T. W., Macduff B. M., Fanslow W. C., Spriggs M. K., Ramsdell F., Alderson M. R. CD40 ligand is a T cell growth factor. Eur J Immunol. 1993 Sep;23(9):2326–2331. doi: 10.1002/eji.1830230941. [DOI] [PubMed] [Google Scholar]
  3. Bailey T. S., Auersperg N., Myrdal S. E. Recloning of SV40 early gene transfected human endothelial cells repeatedly recovers subpopulations with low passage characteristics and morphologies. Biochem Cell Biol. 1994 Mar-Apr;72(3-4):117–125. doi: 10.1139/o94-018. [DOI] [PubMed] [Google Scholar]
  4. Barrett T. B., Shu G., Clark E. A. CD40 signaling activates CD11a/CD18 (LFA-1)-mediated adhesion in B cells. J Immunol. 1991 Mar 15;146(6):1722–1729. [PubMed] [Google Scholar]
  5. Bennett K. L., Jackson D. G., Simon J. C., Tanczos E., Peach R., Modrell B., Stamenkovic I., Plowman G., Aruffo A. CD44 isoforms containing exon V3 are responsible for the presentation of heparin-binding growth factor. J Cell Biol. 1995 Feb;128(4):687–698. doi: 10.1083/jcb.128.4.687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Briscoe D. M., Schoen F. J., Rice G. E., Bevilacqua M. P., Ganz P., Pober J. S. Induced expression of endothelial-leukocyte adhesion molecules in human cardiac allografts. Transplantation. 1991 Feb;51(2):537–539. [PubMed] [Google Scholar]
  7. Carlos T. M., Harlan J. M. Leukocyte-endothelial adhesion molecules. Blood. 1994 Oct 1;84(7):2068–2101. [PubMed] [Google Scholar]
  8. Caux C., Massacrier C., Vanbervliet B., Dubois B., Van Kooten C., Durand I., Banchereau J. Activation of human dendritic cells through CD40 cross-linking. J Exp Med. 1994 Oct 1;180(4):1263–1272. doi: 10.1084/jem.180.4.1263. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. 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]
  10. Damle N. K., Aruffo A. Vascular cell adhesion molecule 1 induces T-cell antigen receptor-dependent activation of CD4+T lymphocytes. Proc Natl Acad Sci U S A. 1991 Aug 1;88(15):6403–6407. doi: 10.1073/pnas.88.15.6403. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Damle N. K., Doyle L. V. Ability of human T lymphocytes to adhere to vascular endothelial cells and to augment endothelial permeability to macromolecules is linked to their state of post-thymic maturation. J Immunol. 1990 Feb 15;144(4):1233–1240. [PubMed] [Google Scholar]
  12. Damle N. K., Eberhardt C., Van der Vieren M. Direct interaction with primed CD4+ CD45R0+ memory T lymphocytes induces expression of endothelial leukocyte adhesion molecule-1 and vascular cell adhesion molecule-1 on the surface of vascular endothelial cells. Eur J Immunol. 1991 Dec;21(12):2915–2923. doi: 10.1002/eji.1830211204. [DOI] [PubMed] [Google Scholar]
  13. Defrance T., Vanbervliet B., Brière F., Durand I., Rousset F., Banchereau J. Interleukin 10 and transforming growth factor beta cooperate to induce anti-CD40-activated naive human B cells to secrete immunoglobulin A. J Exp Med. 1992 Mar 1;175(3):671–682. doi: 10.1084/jem.175.3.671. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Doukas J., Mordes J. P. T lymphocytes capable of activating endothelial cells in vitro are present in rats with autoimmune diabetes. J Immunol. 1993 Feb 1;150(3):1036–1046. [PubMed] [Google Scholar]
  15. Doukas J., Pober J. S. Lymphocyte-mediated activation of cultured endothelial cells (EC). CD4+ T cells inhibit EC class II MHC expression despite secreting IFN-gamma and increasing EC class I MHC and intercellular adhesion molecule-1 expression. J Immunol. 1990 Aug 15;145(4):1088–1098. [PubMed] [Google Scholar]
  16. 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]
  17. Gascan H., Gauchat J. F., Aversa G., Van Vlasselaer P., de Vries J. E. Anti-CD40 monoclonal antibodies or CD4+ T cell clones and IL-4 induce IgG4 and IgE switching in purified human B cells via different signaling pathways. J Immunol. 1991 Jul 1;147(1):8–13. [PubMed] [Google Scholar]
  18. Gordon J., Millsum M. J., Guy G. R., Ledbetter J. A. Resting B lymphocytes can be triggered directly through the CDw40 (Bp50) antigen. A comparison with IL-4-mediated signaling. J Immunol. 1988 Mar 1;140(5):1425–1430. [PubMed] [Google Scholar]
  19. 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]
  20. Hollenbaugh D., Bajorath J., Stenkamp R., Aruffo A. Interaction of P-selectin (CD62) and its cellular ligand: analysis of critical residues. Biochemistry. 1993 Mar 30;32(12):2960–2966. doi: 10.1021/bi00063a006. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. 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]
  23. Kuhlman P., Moy V. T., Lollo B. A., Brian A. A. The accessory function of murine intercellular adhesion molecule-1 in T lymphocyte activation. Contributions of adhesion and co-activation. J Immunol. 1991 Mar 15;146(6):1773–1782. [PubMed] [Google Scholar]
  24. Ledbetter J. A., Shu G., Gallagher M., Clark E. A. Augmentation of normal and malignant B cell proliferation by monoclonal antibody to the B cell-specific antigen BP50 (CDW40). J Immunol. 1987 Feb 1;138(3):788–794. [PubMed] [Google Scholar]
  25. Lederman S., Yellin M. J., Inghirami G., Lee J. J., Knowles D. M., Chess L. Molecular interactions mediating T-B lymphocyte collaboration in human lymphoid follicles. Roles of T cell-B-cell-activating molecule (5c8 antigen) and CD40 in contact-dependent help. J Immunol. 1992 Dec 15;149(12):3817–3826. [PubMed] [Google Scholar]
  26. Luscinskas F. W., Cybulsky M. I., Kiely J. M., Peckins C. S., Davis V. M., Gimbrone M. A., Jr Cytokine-activated human endothelial monolayers support enhanced neutrophil transmigration via a mechanism involving both endothelial-leukocyte adhesion molecule-1 and intercellular adhesion molecule-1. J Immunol. 1991 Mar 1;146(5):1617–1625. [PubMed] [Google Scholar]
  27. Mackay F., Loetscher H., Stueber D., Gehr G., Lesslauer W. Tumor necrosis factor alpha (TNF-alpha)-induced cell adhesion to human endothelial cells is under dominant control of one TNF receptor type, TNF-R55. J Exp Med. 1993 May 1;177(5):1277–1286. doi: 10.1084/jem.177.5.1277. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. 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]
  29. Paulie S., Ehlin-Henriksson B., Mellstedt H., Koho H., Ben-Aissa H., Perlmann P. A p50 surface antigen restricted to human urinary bladder carcinomas and B lymphocytes. Cancer Immunol Immunother. 1985;20(1):23–28. doi: 10.1007/BF00199769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Pelletier R. P., Ohye R. G., Vanbuskirk A., Sedmak D. D., Kincade P., Ferguson R. M., Orosz C. G. Importance of endothelial VCAM-1 for inflammatory leukocytic infiltration in vivo. J Immunol. 1992 Oct 1;149(7):2473–2481. [PubMed] [Google Scholar]
  31. Pober J. S., Cotran R. S. The role of endothelial cells in inflammation. Transplantation. 1990 Oct;50(4):537–544. doi: 10.1097/00007890-199010000-00001. [DOI] [PubMed] [Google Scholar]
  32. Pober J. S., Gimbrone M. A., Jr, Cotran R. S., Reiss C. S., Burakoff S. J., Fiers W., Ault K. A. Ia expression by vascular endothelium is inducible by activated T cells and by human gamma interferon. J Exp Med. 1983 Apr 1;157(4):1339–1353. doi: 10.1084/jem.157.4.1339. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. 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]
  34. Schriever F., Freedman A. S., Freeman G., Messner E., Lee G., Daley J., Nadler L. M. Isolated human follicular dendritic cells display a unique antigenic phenotype. J Exp Med. 1989 Jun 1;169(6):2043–2058. doi: 10.1084/jem.169.6.2043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Simon J. C., Dietrich A., Mielke V., Wuttig C., Vanscheidt W., Linsley P. S., Schöpf E., Sterry W. Expression of the B7/BB1 activation antigen and its ligand CD28 in T-cell-mediated skin diseases. J Invest Dermatol. 1994 Oct;103(4):539–543. doi: 10.1111/1523-1747.ep12395743. [DOI] [PubMed] [Google Scholar]
  36. Springer T. A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell. 1994 Jan 28;76(2):301–314. doi: 10.1016/0092-8674(94)90337-9. [DOI] [PubMed] [Google Scholar]
  37. Tanaka Y., Adams D. H., Hubscher S., Hirano H., Siebenlist U., Shaw S. T-cell adhesion induced by proteoglycan-immobilized cytokine MIP-1 beta. Nature. 1993 Jan 7;361(6407):79–82. doi: 10.1038/361079a0. [DOI] [PubMed] [Google Scholar]
  38. Taylor P. M., Rose M. L., Yacoub M. H., Pigott R. Induction of vascular adhesion molecules during rejection of human cardiac allografts. Transplantation. 1992 Sep;54(3):451–457. doi: 10.1097/00007890-199209000-00013. [DOI] [PubMed] [Google Scholar]
  39. Tohma S., Hirohata S., Lipsky P. E. The role of CD11a/CD18-CD54 interactions in human T cell-dependent B cell activation. J Immunol. 1991 Jan 15;146(2):492–499. [PubMed] [Google Scholar]
  40. Uckun F. M., Gajl-Peczalska K., Myers D. E., Jaszcz W., Haissig S., Ledbetter J. A. Temporal association of CD40 antigen expression with discrete stages of human B-cell ontogeny and the efficacy of anti-CD40 immunotoxins against clonogenic B-lineage acute lymphoblastic leukemia as well as B-lineage non-Hodgkin's lymphoma cells. Blood. 1990 Dec 15;76(12):2449–2456. [PubMed] [Google Scholar]
  41. Van Seventer G. A., Shimizu Y., Horgan K. J., Luce G. E., Webb D., Shaw S. Remote T cell co-stimulation via LFA-1/ICAM-1 and CD2/LFA-3: demonstration with immobilized ligand/mAb and implication in monocyte-mediated co-stimulation. Eur J Immunol. 1991 Jul;21(7):1711–1718. doi: 10.1002/eji.1830210719. [DOI] [PubMed] [Google Scholar]
  42. Young L. S., Dawson C. W., Brown K. W., Rickinson A. B. Identification of a human epithelial cell surface protein sharing an epitope with the C3d/Epstein-Barr virus receptor molecule of B lymphocytes. Int J Cancer. 1989 May 15;43(5):786–794. doi: 10.1002/ijc.2910430508. [DOI] [PubMed] [Google Scholar]
  43. Zhang K., Clark E. A., Saxon A. CD40 stimulation provides an IFN-gamma-independent and IL-4-dependent differentiation signal directly to human B cells for IgE production. J Immunol. 1991 Mar 15;146(6):1836–1842. [PubMed] [Google Scholar]

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

RESOURCES