Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1996 Apr 1;183(4):1603–1612. doi: 10.1084/jem.183.4.1603

Major histocompatibility complex class II-expressing endothelial cells induce allospecific nonresponsiveness in naive T cells

PMCID: PMC2192539  PMID: 8666918

Abstract

The role of endothelial cells (EC) in initiating a primary T cell response is of importance in clinical transplantation and autoimmunity since EC are the first allogeneic target encountered by the recipient's immune system and may display tissue-specific autoantigens in the context of an inflammatory response. In this study, we have investigated the antigen-presenting cell function of human umbilical vein-derived EC (HUVEC), depleted of constitutively major histocompatibility complex class II+ cells and induced to express class II molecules by interferon-gamma. The results show that HUVEC do not express B7 but can support proliferation by antigen-specific T cell clones. In contrast, they were unable to initiate a primary alloresponse using three independent HUVEC cultures and MHC class II- mismatched CD4+ T cells from eight donors. The response to HUVEC was reconstituted by trans-costimulation provided by DAP.3 transfectants expressing human B7.1. Coculture of peripheral blood T cells with EC expressing allogeneic DR molecules had markedly different effects on CD45RO+ and RA+ subsets. Subsequent reactivity of the RO+ T cells was unaffected by exposure to EC, indicating a neutral encounter. In contrast, culture with DR+ EC induced allospecific nonresponsiveness in RA+ T cells.

Full Text

The Full Text of this article is available as a PDF (961.3 KB).

Selected References

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

  1. Bal V., McIndoe A., Denton G., Hudson D., Lombardi G., Lamb J., Lechler R. Antigen presentation by keratinocytes induces tolerance in human T cells. Eur J Immunol. 1990 Sep;20(9):1893–1897. doi: 10.1002/eji.1830200904. [DOI] [PubMed] [Google Scholar]
  2. Boussiotis V. A., Freeman G. J., Gray G., Gribben J., Nadler L. M. B7 but not intercellular adhesion molecule-1 costimulation prevents the induction of human alloantigen-specific tolerance. J Exp Med. 1993 Nov 1;178(5):1753–1763. doi: 10.1084/jem.178.5.1753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Boussiotis V. A., Freeman G. J., Gribben J. G., Daley J., Gray G., Nadler L. M. Activated human B lymphocytes express three CTLA-4 counterreceptors that costimulate T-cell activation. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11059–11063. doi: 10.1073/pnas.90.23.11059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Fermand J. P., Chevalier A., Brouet J. C. Characterization of a monoclonal antibody recognizing a monomorphic determinant of the alpha chain of class II DQ antigens. Scand J Immunol. 1986 Sep;24(3):313–319. doi: 10.1111/j.1365-3083.1986.tb02099.x. [DOI] [PubMed] [Google Scholar]
  5. Fuggle S. V., McWhinnie D. L., Chapman J. R., Taylor H. M., Morris P. J. Sequential analysis of HLA-class II antigen expression in human renal allografts. Induction of tubular class II antigens and correlation with clinical parameters. Transplantation. 1986 Aug;42(2):144–150. doi: 10.1097/00007890-198608000-00008. [DOI] [PubMed] [Google Scholar]
  6. Gaspari A. A., Jenkins M. K., Katz S. I. Class II MHC-bearing keratinocytes induce antigen-specific unresponsiveness in hapten-specific Th1 clones. J Immunol. 1988 Oct 1;141(7):2216–2220. [PubMed] [Google Scholar]
  7. Geppert T. D., Lipsky P. E. Antigen presentation by interferon-gamma-treated endothelial cells and fibroblasts: differential ability to function as antigen-presenting cells despite comparable Ia expression. J Immunol. 1985 Dec;135(6):3750–3762. [PubMed] [Google Scholar]
  8. Gimmi C. D., Freeman G. J., Gribben J. G., Gray G., Nadler L. M. Human T-cell clonal anergy is induced by antigen presentation in the absence of B7 costimulation. Proc Natl Acad Sci U S A. 1993 Jul 15;90(14):6586–6590. doi: 10.1073/pnas.90.14.6586. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Hargreaves R., Logiou V., Lechler R. The primary alloresponse of human CD4+ T cells is dependent on B7 (CD80), augmented by CD58, but relatively uninfluenced by CD54 expression. Int Immunol. 1995 Sep;7(9):1505–1513. doi: 10.1093/intimm/7.9.1505. [DOI] [PubMed] [Google Scholar]
  10. Hughes C. C., Savage C. O., Pober J. S. Endothelial cells augment T cell interleukin 2 production by a contact-dependent mechanism involving CD2/LFA-3 interaction. J Exp Med. 1990 May 1;171(5):1453–1467. doi: 10.1084/jem.171.5.1453. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Jaffe E. A., Nachman R. L., Becker C. G., Minick C. R. Culture of human endothelial cells derived from umbilical veins. Identification by morphologic and immunologic criteria. J Clin Invest. 1973 Nov;52(11):2745–2756. doi: 10.1172/JCI107470. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jenkins M. K., Pardoll D. M., Mizuguchi J., Quill H., Schwartz R. H. T-cell unresponsiveness in vivo and in vitro: fine specificity of induction and molecular characterization of the unresponsive state. Immunol Rev. 1987 Feb;95:113–135. doi: 10.1111/j.1600-065x.1987.tb00502.x. [DOI] [PubMed] [Google Scholar]
  13. Jenkins M. K., Schwartz R. H. Antigen presentation by chemically modified splenocytes induces antigen-specific T cell unresponsiveness in vitro and in vivo. J Exp Med. 1987 Feb 1;165(2):302–319. doi: 10.1084/jem.165.2.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kuiper H., Brouwer M., de Boer M., Parren P., van Lier R. A. Differences in responsiveness to CD3 stimulation between naive and memory CD4+ T cells cannot be overcome by CD28 costimulation. Eur J Immunol. 1994 Sep;24(9):1956–1960. doi: 10.1002/eji.1830240903. [DOI] [PubMed] [Google Scholar]
  15. Lane P., Gerhard W., Hubele S., Lanzavecchia A., McConnell F. Expression and functional properties of mouse B7/BB1 using a fusion protein between mouse CTLA4 and human gamma 1. Immunology. 1993 Sep;80(1):56–61. [PMC free article] [PubMed] [Google Scholar]
  16. Markmann J., Lo D., Naji A., Palmiter R. D., Brinster R. L., Heber-Katz E. Antigen presenting function of class II MHC expressing pancreatic beta cells. Nature. 1988 Dec 1;336(6198):476–479. doi: 10.1038/336476a0. [DOI] [PubMed] [Google Scholar]
  17. Munro C. S., Campbell D. A., Du Bois R. M., Mitchell D. N., Cole P. J., Poulter L. W. Suppression associated lymphocyte markers in lesions of sarcoidosis. Thorax. 1988 Jun;43(6):471–474. doi: 10.1136/thx.43.6.471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Nunez G., Ball E. J., Stastny P. Accessory cell function of human endothelial cells. I. A subpopulation of Ia positive cells is required for antigen presentation. J Immunol. 1983 Aug;131(2):666–673. [PubMed] [Google Scholar]
  19. Page C. S., Holloway N., Smith H., Yacoub M., Rose M. L. Alloproliferative responses of purified CD4+ and CD8+ T cells to endothelial cells in the absence of contaminating accessory cells. Transplantation. 1994 Jun 15;57(11):1628–1637. [PubMed] [Google Scholar]
  20. Quill H., Schwartz R. H. Stimulation of normal inducer T cell clones with antigen presented by purified Ia molecules in planar lipid membranes: specific induction of a long-lived state of proliferative nonresponsiveness. J Immunol. 1987 Jun 1;138(11):3704–3712. [PubMed] [Google Scholar]
  21. Rose M. L., Coles M. I., Griffin R. J., Pomerance A., Yacoub M. H. Expression of class I and class II major histocompatibility antigens in normal and transplanted human heart. Transplantation. 1986 Jun;41(6):776–780. doi: 10.1097/00007890-198606000-00021. [DOI] [PubMed] [Google Scholar]
  22. Savage C. O., Hughes C. C., McIntyre B. W., Picard J. K., Pober J. S. Human CD4+ T cells proliferate to HLA-DR+ allogeneic vascular endothelium. Identification of accessory interactions. Transplantation. 1993 Jul;56(1):128–134. doi: 10.1097/00007890-199307000-00024. [DOI] [PubMed] [Google Scholar]
  23. Savage C. O., Hughes C. C., Pepinsky R. B., Wallner B. P., Freedman A. S., Pober J. S. Endothelial cell lymphocyte function-associated antigen-3 and an unidentified ligand act in concert to provide costimulation to human peripheral blood CD4+ T cells. Cell Immunol. 1991 Oct 1;137(1):150–163. doi: 10.1016/0008-8749(91)90065-j. [DOI] [PubMed] [Google Scholar]
  24. Steinhoff G., Wonigeit K., Pichlmayr R. Analysis of sequential changes in major histocompatibility complex expression in human liver grafts after transplantation. Transplantation. 1988 Feb;45(2):394–401. doi: 10.1097/00007890-198802000-00030. [DOI] [PubMed] [Google Scholar]
  25. Tan P., Anasetti C., Hansen J. A., Melrose J., Brunvand M., Bradshaw J., Ledbetter J. A., Linsley P. S. Induction of alloantigen-specific hyporesponsiveness in human T lymphocytes by blocking interaction of CD28 with its natural ligand B7/BB1. J Exp Med. 1993 Jan 1;177(1):165–173. doi: 10.1084/jem.177.1.165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Wagner C. R., Vetto R. M., Burger D. R. Subcultured human endothelial cells can function independently as fully competent antigen-presenting cells. Hum Immunol. 1985 May;13(1):33–47. doi: 10.1016/0198-8859(85)90025-4. [DOI] [PubMed] [Google Scholar]
  27. Warrens A. N., Zhang J. Y., Sidhu S., Watt D. J., Lombardi G., Sewry C. A., Lechler R. I. Myoblasts fail to stimulate T cells but induce tolerance. Int Immunol. 1994 Jun;6(6):847–853. doi: 10.1093/intimm/6.6.847. [DOI] [PubMed] [Google Scholar]
  28. Yokochi T., Holly R. D., Clark E. A. B lymphoblast antigen (BB-1) expressed on Epstein-Barr virus-activated B cell blasts, B lymphoblastoid cell lines, and Burkitt's lymphomas. J Immunol. 1982 Feb;128(2):823–827. [PubMed] [Google Scholar]

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

RESOURCES