Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1993 Nov 1;178(5):1597–1605. doi: 10.1084/jem.178.5.1597

Costimulator deficient antigen presentation by an endothelial cell line induces a nonproliferative T cell activation response without anergy

PMCID: PMC2191235  PMID: 7693852

Abstract

The ability of endothelial cells to activate helper T (Th) cells by antigen presentation was studied using the murine endothelial cell line SVEC4-10 and antigen-specific murine T cell clones. SEVEC4-10 cells constitutively express vascular cell adhesion molecule 1 but not intercellular adhesion molecule 1. Interferon gamma (IFN-gamma) treatment of these cells induced class II major histocompatibility complex (MHC) expression and antigen-presenting capabilities, but did not alter surface integrin expression. IFN-gamma-treated SVEC4-10 cells were competent at mediating antigen-dependent cytokine production and proliferation of a Th2 clone. In contrast, endothelial antigen presentation to Th1 cells did not stimulate T cell proliferation. The addition of MHC mismatched spleen cells as a source of costimulatory molecules resulted in the ability of the endothelial cells to stimulate Th1 cell proliferation in an antigen-specific manner. The failure of the endothelial cell line alone to support Th1 cell proliferation correlated with the failure to stimulate interleukin 2 (IL-2) gene expression. T cell exposure to the endothelial cells plus antigen resulted in upregulation of IL-2 receptors and an enhanced response to subsequent antigen presentation by splenic antigen-presenting cells. Despite the lack of functional costimulators for IL-2 expression, antigen presentation by the endothelial cell line did not induce Th1 cell anergy, indicating that costimulator deficiency for IL-2 expression is not obligatorily linked to anergy induction. Thus, endothelial cells are capable of presenting antigens to helper T lymphocytes, but stimulate only partial T cell responses. These partial responses may serve to selectively stimulate transmigration of antigen- specific T cells and may enhance functional responses upon subsequent, extravascular antigen exposure.

Full Text

The Full Text of this article is available as a PDF (989.8 KB).

Selected References

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

  1. Beverly B., Kang S. M., Lenardo M. J., Schwartz R. H. Reversal of in vitro T cell clonal anergy by IL-2 stimulation. Int Immunol. 1992 Jun;4(6):661–671. doi: 10.1093/intimm/4.6.661. [DOI] [PubMed] [Google Scholar]
  2. 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]
  3. Damle N. K., Klussman K., Linsley P. S., Aruffo A. Differential costimulatory effects of adhesion molecules B7, ICAM-1, LFA-3, and VCAM-1 on resting and antigen-primed CD4+ T lymphocytes. J Immunol. 1992 Apr 1;148(7):1985–1992. [PubMed] [Google Scholar]
  4. DeSilva D. R., Urdahl K. B., Jenkins M. K. Clonal anergy is induced in vitro by T cell receptor occupancy in the absence of proliferation. J Immunol. 1991 Nov 15;147(10):3261–3267. [PubMed] [Google Scholar]
  5. Fabry Z., Sandor M., Gajewski T. F., Herlein J. A., Waldschmidt M. M., Lynch R. G., Hart M. N. Differential activation of Th1 and Th2 CD4+ cells by murine brain microvessel endothelial cells and smooth muscle/pericytes. J Immunol. 1993 Jul 1;151(1):38–47. [PubMed] [Google Scholar]
  6. Fraser J. D., Weiss A. Regulation of T-cell lymphokine gene transcription by the accessory molecule CD28. Mol Cell Biol. 1992 Oct;12(10):4357–4363. doi: 10.1128/mcb.12.10.4357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Freeman G. J., Gray G. S., Gimmi C. D., Lombard D. B., Zhou L. J., White M., Fingeroth J. D., Gribben J. G., Nadler L. M. Structure, expression, and T cell costimulatory activity of the murine homologue of the human B lymphocyte activation antigen B7. J Exp Med. 1991 Sep 1;174(3):625–631. doi: 10.1084/jem.174.3.625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Galvin F., Freeman G. J., Razi-Wolf Z., Hall W., Jr, Benacerraf B., Nadler L., Reiser H. Murine B7 antigen provides a sufficient costimulatory signal for antigen-specific and MHC-restricted T cell activation. J Immunol. 1992 Dec 15;149(12):3802–3808. [PubMed] [Google Scholar]
  9. 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]
  10. 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]
  11. Geppert T. D., Lipsky P. E. Dissection of defective antigen presentation by interferon-gamma-treated fibroblasts. J Immunol. 1987 Jan 15;138(2):385–392. [PubMed] [Google Scholar]
  12. Go C., Miller J. Differential induction of transcription factors that regulate the interleukin 2 gene during anergy induction and restimulation. J Exp Med. 1992 May 1;175(5):1327–1336. doi: 10.1084/jem.175.5.1327. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Harding F. A., McArthur J. G., Gross J. A., Raulet D. H., Allison J. P. CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones. Nature. 1992 Apr 16;356(6370):607–609. doi: 10.1038/356607a0. [DOI] [PubMed] [Google Scholar]
  14. Hirschberg H., Braathen L. R., Thorsby E. Antigen presentation by vascular endothelial cells and epidermal Langerhans cells: the role of HLA-DR. Immunol Rev. 1982;66:57–77. doi: 10.1111/j.1600-065x.1982.tb00434.x. [DOI] [PubMed] [Google Scholar]
  15. Hirschberg H., Evensen S. A., Henriksen T., Thorsby E. The human mixed lymphocyte-endothelium culture interaction. Transplantation. 1975 Jun;19(6):495–504. doi: 10.1097/00007890-197506000-00008. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Jenkins M. K., Ashwell J. D., Schwartz R. H. Allogeneic non-T spleen cells restore the responsiveness of normal T cell clones stimulated with antigen and chemically modified antigen-presenting cells. J Immunol. 1988 May 15;140(10):3324–3330. [PubMed] [Google Scholar]
  18. Jenkins M. K., Chen C. A., Jung G., Mueller D. L., Schwartz R. H. Inhibition of antigen-specific proliferation of type 1 murine T cell clones after stimulation with immobilized anti-CD3 monoclonal antibody. J Immunol. 1990 Jan 1;144(1):16–22. [PubMed] [Google Scholar]
  19. Jenkins M. K., Pardoll D. M., Mizuguchi J., Chused T. M., Schwartz R. H. Molecular events in the induction of a nonresponsive state in interleukin 2-producing helper T-lymphocyte clones. Proc Natl Acad Sci U S A. 1987 Aug;84(15):5409–5413. doi: 10.1073/pnas.84.15.5409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. Jenkins M. K., Taylor P. S., Norton S. D., Urdahl K. B. CD28 delivers a costimulatory signal involved in antigen-specific IL-2 production by human T cells. J Immunol. 1991 Oct 15;147(8):2461–2466. [PubMed] [Google Scholar]
  22. June C. H., Ledbetter J. A., Linsley P. S., Thompson C. B. Role of the CD28 receptor in T-cell activation. Immunol Today. 1990 Jun;11(6):211–216. doi: 10.1016/0167-5699(90)90085-n. [DOI] [PubMed] [Google Scholar]
  23. Kang S. M., Beverly B., Tran A. C., Brorson K., Schwartz R. H., Lenardo M. J. Transactivation by AP-1 is a molecular target of T cell clonal anergy. Science. 1992 Aug 21;257(5073):1134–1138. doi: 10.1126/science.257.5073.1134. [DOI] [PubMed] [Google Scholar]
  24. Karasuyama H., Melchers F. Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors. Eur J Immunol. 1988 Jan;18(1):97–104. doi: 10.1002/eji.1830180115. [DOI] [PubMed] [Google Scholar]
  25. Koulova L., Clark E. A., Shu G., Dupont B. The CD28 ligand B7/BB1 provides costimulatory signal for alloactivation of CD4+ T cells. J Exp Med. 1991 Mar 1;173(3):759–762. doi: 10.1084/jem.173.3.759. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Koyama K., Fukunishi T., Barcos M., Tanigaki N., Pressman D. Human Ia-like antigens in non-lymphoid organs. Immunology. 1979 Oct;38(2):333–341. [PMC free article] [PubMed] [Google Scholar]
  27. Lanzavecchia A. Antigen-specific interaction between T and B cells. Nature. 1985 Apr 11;314(6011):537–539. doi: 10.1038/314537a0. [DOI] [PubMed] [Google Scholar]
  28. Lichtman A. H., Kurt-Jones E. A., Abbas A. K. B-cell stimulatory factor 1 and not interleukin 2 is the autocrine growth factor for some helper T lymphocytes. Proc Natl Acad Sci U S A. 1987 Feb;84(3):824–827. doi: 10.1073/pnas.84.3.824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Linsley P. S., Brady W., Grosmaire L., Aruffo A., Damle N. K., Ledbetter J. A. Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation. J Exp Med. 1991 Mar 1;173(3):721–730. doi: 10.1084/jem.173.3.721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. 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]
  31. Liu Y., Janeway C. A., Jr Cells that present both specific ligand and costimulatory activity are the most efficient inducers of clonal expansion of normal CD4 T cells. Proc Natl Acad Sci U S A. 1992 May 1;89(9):3845–3849. doi: 10.1073/pnas.89.9.3845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Malek T. R., Robb R. J., Shevach E. M. Identification and initial characterization of a rat monoclonal antibody reactive with the murine interleukin 2 receptor-ligand complex. Proc Natl Acad Sci U S A. 1983 Sep;80(18):5694–5698. doi: 10.1073/pnas.80.18.5694. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. McCarron R. M., Kempski O., Spatz M., McFarlin D. E. Presentation of myelin basic protein by murine cerebral vascular endothelial cells. J Immunol. 1985 May;134(5):3100–3103. [PubMed] [Google Scholar]
  34. McCarron R. M., Racke M., Spatz M., McFarlin D. E. Cerebral vascular endothelial cells are effective targets for in vitro lysis by encephalitogenic T lymphocytes. J Immunol. 1991 Jul 15;147(2):503–508. [PubMed] [Google Scholar]
  35. McCarron R. M., Wang L., Cowan E. P., Spatz M. Class II MHC antigen expression by cultured human cerebral vascular endothelial cells. Brain Res. 1991 Dec 6;566(1-2):325–328. doi: 10.1016/0006-8993(91)91718-g. [DOI] [PubMed] [Google Scholar]
  36. Miyake K., Medina K., Ishihara K., Kimoto M., Auerbach R., Kincade P. W. A VCAM-like adhesion molecule on murine bone marrow stromal cells mediates binding of lymphocyte precursors in culture. J Cell Biol. 1991 Aug;114(3):557–565. doi: 10.1083/jcb.114.3.557. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Montgomery R. A., Dallman M. J. Analysis of cytokine gene expression during fetal thymic ontogeny using the polymerase chain reaction. J Immunol. 1991 Jul 15;147(2):554–560. [PubMed] [Google Scholar]
  38. Mueller D. L., Jenkins M. K., Schwartz R. H. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu Rev Immunol. 1989;7:445–480. doi: 10.1146/annurev.iy.07.040189.002305. [DOI] [PubMed] [Google Scholar]
  39. Natali P. G., De Martino C., Quaranta V., Nicotra M. R., Frezza F., Pellegrino M. A., Ferrone S. Expression of Ia-like antigens in normal human nonlymphoid tissues. Transplantation. 1981 Jan;31(1):75–78. doi: 10.1097/00007890-198101000-00017. [DOI] [PubMed] [Google Scholar]
  40. O'Connell K. A., Edidin M. A mouse lymphoid endothelial cell line immortalized by simian virus 40 binds lymphocytes and retains functional characteristics of normal endothelial cells. J Immunol. 1990 Jan 15;144(2):521–525. [PubMed] [Google Scholar]
  41. 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., Reiss C. S. Lymphocytes recognize human vascular endothelial and dermal fibroblast Ia antigens induced by recombinant immune interferon. Nature. 1983 Oct 20;305(5936):726–729. doi: 10.1038/305726a0. [DOI] [PubMed] [Google Scholar]
  42. Pober J. S., Cotran R. S. Immunologic interactions of T lymphocytes with vascular endothelium. Adv Immunol. 1991;50:261–302. doi: 10.1016/s0065-2776(08)60827-5. [DOI] [PubMed] [Google Scholar]
  43. 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]
  44. Razi-Wolf Z., Freeman G. J., Galvin F., Benacerraf B., Nadler L., Reiser H. Expression and function of the murine B7 antigen, the major costimulatory molecule expressed by peritoneal exudate cells. Proc Natl Acad Sci U S A. 1992 May 1;89(9):4210–4214. doi: 10.1073/pnas.89.9.4210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Reiser H., Freeman G. J., Razi-Wolf Z., Gimmi C. D., Benacerraf B., Nadler L. M. Murine B7 antigen provides an efficient costimulatory signal for activation of murine T lymphocytes via the T-cell receptor/CD3 complex. Proc Natl Acad Sci U S A. 1992 Jan 1;89(1):271–275. doi: 10.1073/pnas.89.1.271. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Rock K. L., Benacerraf B., Abbas A. K. Antigen presentation by hapten-specific B lymphocytes. I. Role of surface immunoglobulin receptors. J Exp Med. 1984 Oct 1;160(4):1102–1113. doi: 10.1084/jem.160.4.1102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Sakai K., Tabira T., Endoh M., Steinman L. Ia expression in chronic relapsing experimental allergic encephalomyelitis induced by long-term cultured T cell lines in mice. Lab Invest. 1986 Mar;54(3):345–352. [PubMed] [Google Scholar]
  48. 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]
  49. Schwartz R. H. A cell culture model for T lymphocyte clonal anergy. Science. 1990 Jun 15;248(4961):1349–1356. doi: 10.1126/science.2113314. [DOI] [PubMed] [Google Scholar]
  50. Schwartz R. H. Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy. Cell. 1992 Dec 24;71(7):1065–1068. doi: 10.1016/s0092-8674(05)80055-8. [DOI] [PubMed] [Google Scholar]
  51. Schwartz R. H., Mueller D. L., Jenkins M. K., Quill H. T-cell clonal anergy. Cold Spring Harb Symp Quant Biol. 1989;54(Pt 2):605–610. doi: 10.1101/sqb.1989.054.01.072. [DOI] [PubMed] [Google Scholar]
  52. Stallcup K. C., Springer T. A., Mescher M. F. Characterization of an anti-H-2 monoclonal antibody and its use in large-scale antigen purification. J Immunol. 1981 Sep;127(3):923–930. [PubMed] [Google Scholar]
  53. Steinman R. M. The dendritic cell system and its role in immunogenicity. Annu Rev Immunol. 1991;9:271–296. doi: 10.1146/annurev.iy.09.040191.001415. [DOI] [PubMed] [Google Scholar]
  54. Unanue E. R., Allen P. M. The basis for the immunoregulatory role of macrophages and other accessory cells. Science. 1987 May 1;236(4801):551–557. doi: 10.1126/science.2437650. [DOI] [PubMed] [Google Scholar]
  55. 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]
  56. Van Seventer G. A., Shimizu Y., Horgan K. J., Shaw S. The LFA-1 ligand ICAM-1 provides an important costimulatory signal for T cell receptor-mediated activation of resting T cells. J Immunol. 1990 Jun 15;144(12):4579–4586. [PubMed] [Google Scholar]
  57. Wagner C. R., Vetto R. M., Burger D. R. The mechanism of antigen presentation by endothelial cells. Immunobiology. 1984 Dec;168(3-5):453–469. doi: 10.1016/S0171-2985(84)80130-8. [DOI] [PubMed] [Google Scholar]
  58. Williams I. R., Unanue E. R. Characterization of accessory cell costimulation of Th1 cytokine synthesis. J Immunol. 1991 Dec 1;147(11):3752–3760. [PubMed] [Google Scholar]
  59. Williams I. R., Unanue E. R. Costimulatory requirements of murine Th1 clones. The role of accessory cell-derived signals in responses to anti-CD3 antibody. J Immunol. 1990 Jul 1;145(1):85–93. [PubMed] [Google Scholar]
  60. de Waal R. M., Bogman M. J., Maass C. N., Cornelissen L. M., Tax W. J., Koene R. A. Variable expression of Ia antigens on the vascular endothelium of mouse skin allografts. Nature. 1983 Jun 2;303(5916):426–429. doi: 10.1038/303426a0. [DOI] [PubMed] [Google Scholar]
  61. van Seventer G. A., Shimizu Y., Shaw S. Roles of multiple accessory molecules in T-cell activation. Curr Opin Immunol. 1991 Jun;3(3):294–303. doi: 10.1016/0952-7915(91)90027-x. [DOI] [PubMed] [Google Scholar]

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

RESOURCES