Abstract
We have demonstrated that endothelial cells (EC) augment IL-2 production by PHA-stimulated PBMC or purified CD4+ T cells and that the increase is apparent both in the amount of soluble IL-2 secreted and in the level of specific mRNA detectable by Northern blot hybridization. The ability of EC to affect levels of IL-2 cannot be reproduced by soluble factors, including the cytokines IL-1, IL-6, IFN-gamma, or TNF, conditioned medium from resting EC or IL-1, IFN-gamma- or TNF-treated EC, or from resting PBMC + EC cultures. Separation of the EC and PBMC by a Transwell membrane demonstrated that cell contact was required for augmentation of IL-2 synthesis and that this effect was unlikely to be mediated by a short-lived soluble signal. The cell-cell interaction required the ligand pair CD2/LFA-3, since augmentation could be inhibited by antibodies to these structures. Antibodies to ICAM-1, LFA- 1, CD4, and MHC class II were without effect. A contact-dependent pathway involving CD2/LFA-3 interactions also may be used by EC to augment IL-2 production from T cells stimulated more specifically through the TCR/CD3 complex with antibody OKT3. This pathway provides a proliferative advantage to T cells stimulated with OKT3 in the presence of EC and may also be involved in the proliferative response of resting T cells to allogeneic class II MHC-expressing EC. We propose that EC augmentation of T cell IL-2 synthesis may be critical in the ability of EC to elicit primary T cell antigen responses and may have consequences for the development of localized cell-mediated immune reactions.
Full Text
The Full Text of this article is available as a PDF (907.3 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Ceuppens J. L., Baroja M. L., Lorre K., Van Damme J., Billiau A. Human T cell activation with phytohemagglutinin. The function of IL-6 as an accessory signal. J Immunol. 1988 Dec 1;141(11):3868–3874. [PubMed] [Google Scholar]
- Garman R. D., Jacobs K. A., Clark S. C., Raulet D. H. B-cell-stimulatory factor 2 (beta 2 interferon) functions as a second signal for interleukin 2 production by mature murine T cells. Proc Natl Acad Sci U S A. 1987 Nov;84(21):7629–7633. doi: 10.1073/pnas.84.21.7629. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Geppert T. D., Lipsky P. E. Accessory cell independent proliferation of human T4 cells stimulated by immobilized monoclonal antibodies to CD3. J Immunol. 1987 Mar 15;138(6):1660–1666. [PubMed] [Google Scholar]
- 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]
- 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]
- Gery I., Gershon R. K., Waksman B. H. Potentiation of the T-lymphocyte response to mitogens. I. The responding cell. J Exp Med. 1972 Jul 1;136(1):128–142. doi: 10.1084/jem.136.1.128. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Gimbrone M. A., Jr Culture of vascular endothelium. Prog Hemost Thromb. 1976;3:1–28. [PubMed] [Google Scholar]
- Granelli-Piperno A., Keane M., Steinman R. M. Growth factor production and requirements during the proliferative response of human T lymphocytes to anti-CD3 monoclonal antibody. J Immunol. 1989 Jun 15;142(12):4138–4143. [PubMed] [Google Scholar]
- Guinan E. C., Smith B. R., Davies P. F., Pober J. S. Cytoplasmic transfer between endothelium and lymphocytes: quantitation by flow cytometry. Am J Pathol. 1988 Sep;132(3):406–409. [PMC free article] [PubMed] [Google Scholar]
- Guinan E. C., Smith B. R., Doukas J. T., Miller R. A., Pober J. S. Vascular endothelial cells enhance T cell responses by markedly augmenting IL-2 concentrations. Cell Immunol. 1989 Jan;118(1):166–177. doi: 10.1016/0008-8749(89)90366-3. [DOI] [PubMed] [Google Scholar]
- Halvorsen R., Leivestad T., Gaudernack G., Thorsby E. Accessory cell-dependent T-cell activation via Ti-CD3. Involvement of CD2-LFA-3 interactions. Scand J Immunol. 1988 Sep;28(3):277–284. doi: 10.1111/j.1365-3083.1988.tb01449.x. [DOI] [PubMed] [Google Scholar]
- Hara T., Fu S. M., Hansen J. A. Human T cell activation. II. A new activation pathway used by a major T cell population via a disulfide-bonded dimer of a 44 kilodalton polypeptide (9.3 antigen). J Exp Med. 1985 Jun 1;161(6):1513–1524. doi: 10.1084/jem.161.6.1513. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Huet S., Groux H., Caillou B., Valentin H., Prieur A. M., Bernard A. CD44 contributes to T cell activation. J Immunol. 1989 Aug 1;143(3):798–801. [PubMed] [Google Scholar]
- Inaba K., Romani N., Steinman R. M. An antigen-independent contact mechanism as an early step in T cell-proliferative responses to dendritic cells. J Exp Med. 1989 Aug 1;170(2):527–542. doi: 10.1084/jem.170.2.527. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jirik F. R., Podor T. J., Hirano T., Kishimoto T., Loskutoff D. J., Carson D. A., Lotz M. Bacterial lipopolysaccharide and inflammatory mediators augment IL-6 secretion by human endothelial cells. J Immunol. 1989 Jan 1;142(1):144–147. [PubMed] [Google Scholar]
- June C. H., Ledbetter J. A., Lindsten T., Thompson C. B. Evidence for the involvement of three distinct signals in the induction of IL-2 gene expression in human T lymphocytes. J Immunol. 1989 Jul 1;143(1):153–161. [PubMed] [Google Scholar]
- Kaplan G., Nusrat A., Witmer M. D., Nath I., Cohn Z. A. Distribution and turnover of Langerhans cells during delayed immune responses in human skin. J Exp Med. 1987 Mar 1;165(3):763–776. doi: 10.1084/jem.165.3.763. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kurt-Jones E. A., Fiers W., Pober J. S. Membrane interleukin 1 induction on human endothelial cells and dermal fibroblasts. J Immunol. 1987 Oct 1;139(7):2317–2324. [PubMed] [Google Scholar]
- Lansdorp P. M., Aarden L. A., Calafat J., Zeiljemaker W. P. A growth-factor dependent B-cell hybridoma. Curr Top Microbiol Immunol. 1986;132:105–113. doi: 10.1007/978-3-642-71562-4_14. [DOI] [PubMed] [Google Scholar]
- Larsson E. L., Iscove N. N., Coutinho A. Two distinct factors are required for induction of T-cell growth. Nature. 1980 Feb 14;283(5748):664–666. doi: 10.1038/283664a0. [DOI] [PubMed] [Google Scholar]
- Libby P., Ordovas J. M., Auger K. R., Robbins A. H., Birinyi L. K., Dinarello C. A. Endotoxin and tumor necrosis factor induce interleukin-1 gene expression in adult human vascular endothelial cells. Am J Pathol. 1986 Aug;124(2):179–185. [PMC free article] [PubMed] [Google Scholar]
- Moingeon P., Chang H. C., Wallner B. P., Stebbins C., Frey A. Z., Reinherz E. L. CD2-mediated adhesion facilitates T lymphocyte antigen recognition function. Nature. 1989 May 25;339(6222):312–314. doi: 10.1038/339312a0. [DOI] [PubMed] [Google Scholar]
- Moretta A., Pantaleo G., Lopez-Botet M., Moretta L. Involvement of T44 molecules in an antigen-independent pathway of T cell activation. Analysis of the correlations to the T cell antigen-receptor complex. J Exp Med. 1985 Sep 1;162(3):823–838. doi: 10.1084/jem.162.3.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods. 1983 Dec 16;65(1-2):55–63. doi: 10.1016/0022-1759(83)90303-4. [DOI] [PubMed] [Google Scholar]
- Nathan C. F., Kaplan G., Levis W. R., Nusrat A., Witmer M. D., Sherwin S. A., Job C. K., Horowitz C. R., Steinman R. M., Cohn Z. A. Local and systemic effects of intradermal recombinant interferon-gamma in patients with lepromatous leprosy. N Engl J Med. 1986 Jul 3;315(1):6–15. doi: 10.1056/NEJM198607033150102. [DOI] [PubMed] [Google Scholar]
- 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]
- Pober J. S., Collins T., Gimbrone M. A., Jr, Libby P., Reiss C. S. Inducible expression of class II major histocompatibility complex antigens and the immunogenicity of vascular endothelium. Transplantation. 1986 Feb;41(2):141–146. doi: 10.1097/00007890-198602000-00001. [DOI] [PubMed] [Google Scholar]
- Scheurich P., Thoma B., Ucer U., Pfizenmaier K. Immunoregulatory activity of recombinant human tumor necrosis factor (TNF)-alpha: induction of TNF receptors on human T cells and TNF-alpha-mediated enhancement of T cell responses. J Immunol. 1987 Mar 15;138(6):1786–1790. [PubMed] [Google Scholar]
- Sironi M., Breviario F., Proserpio P., Biondi A., Vecchi A., Van Damme J., Dejana E., Mantovani A. IL-1 stimulates IL-6 production in endothelial cells. J Immunol. 1989 Jan 15;142(2):549–553. [PubMed] [Google Scholar]
- Smith K. A. Interleukin-2: inception, impact, and implications. Science. 1988 May 27;240(4856):1169–1176. doi: 10.1126/science.3131876. [DOI] [PubMed] [Google Scholar]
- Thornton S. C., Mueller S. N., Levine E. M. Human endothelial cells: use of heparin in cloning and long-term serial cultivation. Science. 1983 Nov 11;222(4624):623–625. doi: 10.1126/science.6635659. [DOI] [PubMed] [Google Scholar]
- Umetsu D. T., Katzen D., Jabara H. H., Geha R. S. Antigen presentation by human dermal fibroblasts: activation of resting T lymphocytes. J Immunol. 1986 Jan;136(2):440–445. [PubMed] [Google Scholar]
- Umetsu D. T., Pober J. S., Jabara H. H., Fiers W., Yunis E. J., Burakoff S. J., Reiss C. S., Geha R. S. Human dermal fibroblasts present tetanus toxoid antigen to antigen-specific T cell clones. J Clin Invest. 1985 Jul;76(1):254–260. doi: 10.1172/JCI111955. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wacholtz M. C., Patel S. S., Lipsky P. E. Patterns of costimulation of T cell clones by cross-linking CD3, CD4/CD8, and class I MHC molecules. J Immunol. 1989 Jun 15;142(12):4201–4212. [PubMed] [Google Scholar]
- Watson J. Continuous proliferation of murine antigen-specific helper T lymphocytes in culture. J Exp Med. 1979 Dec 1;150(6):1510–1519. doi: 10.1084/jem.150.6.1510. [DOI] [PMC free article] [PubMed] [Google Scholar]