Lymphocyte Interactions with Endothelial Cells

  • Jordan S. Pober
Part of the GWUMC Department of Biochemistry Annual Spring Symposia book series (GWUN)


The endothelial lining of the vasculature forms the interface of the vessel wall and peripheral tissues with the blood. Therefore, circulating lymphocytes must contact endothelial cells as they home to a site of immune inflammation. Morphologically, both lymphocytes and endothelial cells appear “activated” during this encounter, but the details and mechanisms of the activation processes are not fully understood. We have used cultured human endothelial cells (HEC) and peripheral blood mononuclear cells (PBMC) to study potential interactions between these cell types. In bulk coculture, HEC activate allogeneic T cells, leading PBMC to proliferate. In contrast, dermal fibroblasts or vascular smooth muscle cells do not induce allogeneic PBMC proliferation. The HEC modify the response of PBMC to exogenous stimulation; inclusion of HEC in a culture of PBMC stimulated by phytohemagglutinin leads to increased PBMC proliferation and up to ten-fold or greater enhancement of interleukin 2 production. The phenotypes in the proliferating PBMC are altered by the presence of HEC. Prior to coculture with PBMC, HEC do not express class II major histocompatibility complex (MHC) antigens, the major stimulus of PBMC proliferation to allogeneic PBMC. However, within 1–2 days of coculture, the HEC uniformly express class II molecules. Since PBMC proliferation begins on day 4 or 5, the induced HEC class II molecules could be involved in the T cell activation. Immune interferon (IFN-7), a mediator secreted by activated T cells, mimics the effect of coculture by inducing class II molecules. All three class II loci (DR, DP, DQ) are activated, leading to de novo appearance of mRNA and surface antigen expression. The IFN-7 also induces quantitatively comparable expression of class II molecules on dermal fibroblasts or smooth muscle cells, but such cells still fail to stimulate allogeneic PBMC, even in the presence of exogenous interleukin 1. It appears unlikely that this “defect” resides in tissue-specific structural differences of the class II molecules, since IFN-γ-treated dermal fibroblasts are lysed by class-II-specific cytolytic T lymphocyte clones and activate cloned helper T cells. Coculture of HEC with PBMC or treatment with IFN-γ causes cultured HEC to undergo morphological changes. Specifically, IFN-γ-treated HEC become plump and elongated, overlap, rearrange their actin filaments, and lose their matrix-associated fibronectin. These morphological changes are not seen with IFN-γ-treated dermal fibroblasts, nor can they be induced in HEC cultures by nonimmune interferons (IFN-α,ß). Tumor necrosis factor (TNF), a product of activated monocytes, causes IFN-γ-like morphological changes in HEC cultures. Low concentrations of TNF and IFN-γ act synergistically, whereas higher concentrations of these mediators in combination produce unique effects. Murine monoclonal antibody H4/18 detects an antigen induced on HEC by coculture with PBMC. In contrast to the modulation of MHC antigens, which plateau after several days and persist, the antigen recognized by H4/18 peaks in several hours and disappears. This transient induction can be mimicked by TNF and interleukin 1, but not IFN--y. and parallels several othcr transicntly expressed HEC properties such as procoagulant activity and leukocyte adhesion. These studies demonstrate that the interaction of lymphocytes and endothelium in culiure alters the behavior and phenotype of both cells and suggest that lymphokines, acting separatcly and in combination. may mediale many of these interactions.


Endothelial Cell Major Histocompatibility Complex Peripheral Blood Mononuclear Cell Dermal Fibroblast Human Endothelial Cell 
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. Bevilacqua, M. P., Pober, J. S., Majeau, G. R., Cotran, R. S., and, Gimbrone, M. A., Jr., 1984, Interleukin 1 (IL-1) induces biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells, J. Exp. Med. 160:618–623.PubMedCrossRefGoogle Scholar
  2. Bevilacqua, M. P., Pober, J. S., Wheeler, E. W., Cotran, R. S., and, Gimbrone, M. A., Jr., 1985a, Interleukin 1 acts on cultured human vascular endothelial cells to increase the adhesion of polymorphonuclear leukocytes, monocytes and related leukocyte cell lines, J. Clin. Invest. 76:2003–2011.PubMedCrossRefGoogle Scholar
  3. Bevilacqua, M. P., Pober, J. S., Wheeler, E. W., Cotran, R. S., and, Gimbrone, M. A., Jr., 1985b, Interleukin 1 (IL-1) activation of vascular endothelium: Effects on procoagulant activity and leukocyte adhesion, Am. J. Pathol. 121:393–403.Google Scholar
  4. Bevilacqua, M. P., Pober, J. S., Majeau, G. R., Fiers, W., Cotran, R. S., and, Gimbrone, M. A., Jr., 1986, Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: Characterization and comparison with the actions of interleukin 1, Proc. Natl. Acad. Sci. U.S.A. 83:4533–4537.PubMedCrossRefGoogle Scholar
  5. Cavender, D. E., Haskard, D. O., Joseph, B., and Ziff, M., 1986, Interleukin 1 increases the binding of human B and T lymphocytes to endothelial cell monolayers, J. Immunol. 136:203–207.PubMedGoogle Scholar
  6. Collins, T., Korman, A. J., Wake, C. T., Boss, J. M., Kappes, D. J., Fiers, W., Ault, K. A., Gimbrone, M. A., Jr., Strominger, J. L., and Pober, J. S., 1984a, Immune interferon activates multiple class II major histocompatibility complex genes and the associated invariant chain gene in human endothelial cells and dermal fibroblasts, Proc. Natl. Acad. Sci. U.S.A. 81:4917–4921.PubMedCrossRefGoogle Scholar
  7. Collins, T., Krensky, A. M., Clayberger, C., Fiers, W., Gimbrone, M. A., Jr., Burakoff, S. J., and Pober, J. S., 1984b, Human cytolytic T lymphocytes interactions with vascular endothelium and fibroblasts: Role of effector and target cell molecules, J. Immunol. 133:1878–1884.PubMedGoogle Scholar
  8. Collins, T., Lapierre, L. A., Fiers, W., Strominger, J. L., and Pober, J. S., 1986, Recombinant tumor necrosis factor increases mRNA levels and surface expression of HLA-A,B antigens in vascular endothelial cells and dermal fibroblasts in vitro, Proc. Natl. Acad. Sci. U.S.A. 83:446–450.PubMedCrossRefGoogle Scholar
  9. Cotran, R. S., Gimbrone, M. A., Jr., Bevilacqua, M. P., Mendrick, D. L., and Pober, J. S., 1986, Induction and detection of a human endothelial activation antigen in vivo, J. Exp. Med. 164:661–666.PubMedCrossRefGoogle Scholar
  10. Dvorak, H. F., Galli, S. J., and Dvorak, A. M., 1986, Cellular and vascular manifestations of cell-mediated immunity, Hum. Pathol. 47:122–137.CrossRefGoogle Scholar
  11. Gamble, J. R., Harlan, J. M., Klebanoff, S. J., and Vadas, M. A., 1985, Stimulation of the adherence of neutrophils to umbilical vein endothelium by recombinant human tumor necrosis factor, Proc. Natl. Acad. Sci. U.S.A. 82:8667–8671.PubMedCrossRefGoogle Scholar
  12. Guinan, E. C., and Pober, J. S., 1986, Interleukin 2 secretion by lectin-activated human blood lymphocytes is markedly augmented by vascular endothelial cells, Fed. Proc. 45:724.Google Scholar
  13. Hirschberg, H., Evensen, S. A., Henriksen, T., and Thorsby, E., 1975, The human mixed lymphocyte-endothelium culture interaction, Transplantation 19:495–504.PubMedCrossRefGoogle Scholar
  14. Pober, J. S., and Gimbrone, M. A., Jr., 1982, Expression of la-like antigens by human vascular endothelial cells is inducible in vitro, Proc. Natl. Acad. Sci. U.S.A. 79:6641–6645.PubMedCrossRefGoogle Scholar
  15. Pober, J. S., Collins, T., Gimbrone, M. A., Jr., Cotran, R. S., Gitlin, J. D., Fiers, W., Clayberger, C., Krensky, A. M., Burakoff, S. J., and Reiss, C. S., 1983a, Lymphocytes recognize human vascular endothelial and dermal fibroblast Ia antigens induced by recombinant immune interferon, Nature 305:726–729.PubMedCrossRefGoogle Scholar
  16. Pober, J. S., Gimbronc, M. A., Jr., Cotran, R. S., Reiss, C. S., Burakoff, S. J., Fiers, W., and Ault, K. A., 1983b, la expression by vascular endothelium is inducible by activated T cells and by human interferon, J. Exp. Med. 157:1339–1353.PubMedCrossRefGoogle Scholar
  17. Pober, J. S., Gimbrone, M. A., Jr., Collins, T., Cotran, R. S., Ault, K. A., Fiers, W., Krensky, A. M., Clayberger, C., Reiss, C. S., and Burakoff, S. J., 1984, Interactions of T lymphocytes with human vascular endothelial cells: Role of endothelial cell surface antigens, lmmunobiology 168:483–494.CrossRefGoogle Scholar
  18. Pober, J. S., Bevilacqua, M. P., Mendrick, D. L., Lapierre, L. A., Fiers, W., and Gimbrone, M. A., Jr., 1986a, Two distinct monokines, interleukin 1 and tumor necrosis factor, each independently induce biosynthesis and transient expression of the same antigen on the surface of cultured human vascular endothelial cells, J. Immunol. 136:1680–1687.PubMedGoogle Scholar
  19. Pober, J. S., Collins, T., Gimbrone, M. A., Jr., Libby, P., and Reiss, C. S., 1986b, Inducible expression of class II major histocompatibility complex antigens and the immunogenicity of vascular endothelium, Transplantation 41:141–146.PubMedCrossRefGoogle Scholar
  20. Pober, J. S., Gimbrone, M. A., Jr., Lapierre, L. A., Mendrick, D. L., Fiers, W., Rothlein, R., and Springer, T. A., 1986c, Activation of human endothelial cells by lymphokines: Overlapping patterns of antigenic modulation by interleukin 1, tumor necrosis factor and immune interferon, J. Immunol. 137:1893–1896.Google Scholar
  21. Stolpen, A. H., Guinan, E. C., Fiers, W., and Pober, J. S., 1986, Recombinant tumor necrosis factor and immune interferon act singly and in combination to reorganize human vascular endothelial cell monolayers. Am. J. Pathol. 123:16–24.PubMedGoogle Scholar
  22. Umetsu, D. T., Pober, J. S., Jabara, H. H., Fiers, W., Yunis, E., Burakoff, S. J., Reiss, C. S., and Geha, R. S., 1985, Human dermal fibroblasts present tetanus toxoid antigen to antigen specific T cell clones, J. Clin. Invest. 76:254–260.PubMedCrossRefGoogle Scholar
  23. Yu, C. L., Haskard, D. O., Cavender, D., Johnson, A. R., and Ziff, M., 1985, Human gamma interferon increases the binding of T lymphocytes to endothelial cells, Clin. Exp. Immunol. 62:554– 560.PubMedGoogle Scholar

Copyright information

© Plenum Press, New York 1987

Authors and Affiliations

  • Jordan S. Pober
    • 1
  1. 1.Department of PathologyBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA

Personalised recommendations