Skip to main content
PMC home page
The Journal of Experimental Medicine logoLink to The Journal of Experimental Medicine
. 1986 Jul 1;164(1):131–143. doi: 10.1084/jem.164.1.131

Supernatants of human leukocytes contain mediator, different from interferon gamma, which induces expression of MHC class II antigens

PMCID: PMC2188190  PMID: 2941512

Abstract

In this report, data are presented on the regulation of MHC class II antigen expression by a mediator present in supernatants of human mixed leukocyte cultures (MLC-SN), and which is different from IFN-gamma. The capacity of supernatants to induce antigen expression did not correspond to titers of IFN-gamma. Removal of IFN-gamma using either dialysis against pH 2 or neutralizing mAb against human IFN-gamma did not abrogate the MHC class II antigen expression-inducing capacity of MLC-SN when tested on adenocarcinoma cell lines, kidney epithelial cells, and fibroblasts in vitro in an indirect immunofluorescence assay. Therefore, supernatants of human leukocytes contain a mediator, different from IFN-gamma, which induces expression of MHC class II antigens. Dose-response studies revealed that the mediator is produced after allogeneic and lectin stimulation of human leukocytes, and by unstimulated leukocytes. Activation of leukocytes resulted in increased titers of the mediator. The mediator markedly enhances expression of both HLA-DR and HLA-DQ antigens, whereas IFN-gamma had a similar effect on HLA-DR antigens, and only a minor effect on HLA-DQ antigens. Interaction of the mediator and IFN-gamma resulted in a potentiating effect of these two factors on MHC class II antigen expression. Biochemical analysis revealed a mediator, distinguishable by FPLC from IL-1, IL-2, and human IFN-gamma, and which has a molecular mass of 32 kD.

Full Text

The Full Text of this article is available as a PDF (747.0 KB).

Selected References

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

  1. Ballardini G., Mirakian R., Bianchi F. B., Pisi E., Doniach D., Bottazzo G. F. Aberrant expression of HLA-DR antigens on bileduct epithelium in primary biliary cirrhosis: relevance to pathogenesis. Lancet. 1984 Nov 3;2(8410):1009–1013. doi: 10.1016/s0140-6736(84)91108-5. [DOI] [PubMed] [Google Scholar]
  2. Barnstable C. J., Bodmer W. F., Brown G., Galfre G., Milstein C., Williams A. F., Ziegler A. Production of monoclonal antibodies to group A erythrocytes, HLA and other human cell surface antigens-new tools for genetic analysis. Cell. 1978 May;14(1):9–20. doi: 10.1016/0092-8674(78)90296-9. [DOI] [PubMed] [Google Scholar]
  3. Basham T. Y., Merigan T. C. Recombinant interferon-gamma increases HLA-DR synthesis and expression. J Immunol. 1983 Apr;130(4):1492–1494. [PubMed] [Google Scholar]
  4. Belsito D. V., Sanchez M. R., Baer R. L., Valentine F., Thorbecke G. J. Reduced Langerhans' cell Ia antigen and ATPase activity in patients with the acquired immunodeficiency syndrome. N Engl J Med. 1984 May 17;310(20):1279–1282. doi: 10.1056/NEJM198405173102002. [DOI] [PubMed] [Google Scholar]
  5. Brodsky F. M., Parham P., Bodmer W. F. Monoclonal antibodies to HLA--DRw determinants. Tissue Antigens. 1980 Jul;16(1):30–48. doi: 10.1111/j.1399-0039.1980.tb00285.x. [DOI] [PubMed] [Google 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., Pober J. S. 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. 1984 Aug;81(15):4917–4921. doi: 10.1073/pnas.81.15.4917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. De Ley M., Van Damme J., Billiau A., De Somer P. The preparation of antibodies directed against human immune interferon. J Virol Methods. 1981 Oct;3(3):149–153. doi: 10.1016/0166-0934(81)90049-5. [DOI] [PubMed] [Google Scholar]
  8. Devos R., Cheroutre H., Taya Y., Degrave W., Van Heuverswyn H., Fiers W. Molecular cloning of human immune interferon cDNA and its expression in eukaryotic cells. Nucleic Acids Res. 1982 Apr 24;10(8):2487–2501. doi: 10.1093/nar/10.8.2487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Devos R., Plaetinck G., Cheroutre H., Simons G., Degrave W., Tavernier J., Remaut E., Fiers W. Molecular cloning of human interleukin 2 cDNA and its expression in E. coli. Nucleic Acids Res. 1983 Jul 11;11(13):4307–4323. doi: 10.1093/nar/11.13.4307. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Doveren R. F., van der Linden C. J., Spronken E. E., Groenewegen G., Buurman W. A. Canine MHC-class II antigens on B and T lymphocytes. Tissue Antigens. 1986 Feb;27(2):87–98. doi: 10.1111/j.1399-0039.1986.tb01503.x. [DOI] [PubMed] [Google Scholar]
  11. Fuggle S. V., Errasti P., Daar A. S., Fabre J. W., Ting A., Morris P. J. Localization of major histocompatibility complex (HLA-ABC and DR) antigens in 46 kidneys. Differences in HLA-DR staining of tubules among kidneys. Transplantation. 1983 Apr;35(4):385–390. doi: 10.1097/00007890-198304000-00024. [DOI] [PubMed] [Google Scholar]
  12. Groenewegen G., Buurman W. A., van der Linden C. J. Lymphokine dependence of in vivo expression of MHC class II antigens by endothelium. Nature. 1985 Jul 25;316(6026):361–363. doi: 10.1038/316361a0. [DOI] [PubMed] [Google Scholar]
  13. Hall B. M., Bishop G. A., Duggin G. G., Horvath J. S., Philips J., Tiller D. J. Increased expression of HLA-DR antigens on renal tubular cells in renal transplants: relevance to the rejection response. Lancet. 1984 Aug 4;2(8397):247–251. doi: 10.1016/s0140-6736(84)90297-6. [DOI] [PubMed] [Google Scholar]
  14. Hanafusa T., Pujol-Borrell R., Chiovato L., Russell R. C., Doniach D., Bottazzo G. F. Aberrant expression of HLA-DR antigen on thyrocytes in Graves' disease: relevance for autoimmunity. Lancet. 1983 Nov 12;2(8359):1111–1115. doi: 10.1016/s0140-6736(83)90628-1. [DOI] [PubMed] [Google Scholar]
  15. Hart D. N., Fuggle S. V., Williams K. A., Fabre J. W., Ting A., Morris P. J. Localization of HLA-ABC and DR antigens in human kidney. Transplantation. 1981 Jun;31(6):428–433. doi: 10.1097/00007890-198106000-00005. [DOI] [PubMed] [Google Scholar]
  16. Koning F., Schreuder I., Giphart M., Bruning H. A mouse monoclonal antibody detecting a DR-related MT2-like specificity: serology and biochemistry. Hum Immunol. 1984 Apr;9(4):221–230. doi: 10.1016/0198-8859(84)90027-2. [DOI] [PubMed] [Google Scholar]
  17. Lampert I. A., Suitters A. J., Chisholm P. M. Expression of Ia antigen on epidermal keratinocytes in graft-versus-host disease. Nature. 1981 Sep 10;293(5828):149–150. doi: 10.1038/293149a0. [DOI] [PubMed] [Google Scholar]
  18. Lonai P., Steinman L. Physiological regulation of antigen binding to T cells: role of a soluble macrophage factor and of interferon. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5662–5666. doi: 10.1073/pnas.74.12.5662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mason D. W., Dallman M., Barclay A. N. Graft-versus-host disease induces expression of Ia antigen in rat epidermal cells and gut epithelium. Nature. 1981 Sep 10;293(5828):150–151. doi: 10.1038/293150a0. [DOI] [PubMed] [Google Scholar]
  20. McKenzie J. L., Fabre J. W. Studies with a monoclonal antibody on the distribution of Thy-1 in the lymphoid and extracellular connective tissues of the dog. Transplantation. 1981 Apr;31(4):275–282. doi: 10.1097/00007890-198104000-00009. [DOI] [PubMed] [Google Scholar]
  21. Pawelec G., Ziegler A., Wernet P. Dissection of human allostimulatory determinants with cloned T cells: stimulation inhibition by monoclonal antibodies TU22, 34, 35, 36, 37, 39, 43, and 58 against distinct human MHC class II molecules. Hum Immunol. 1985 Mar;12(3):165–176. doi: 10.1016/0198-8859(85)90333-7. [DOI] [PubMed] [Google Scholar]
  22. Pfizenmaier K., Bartsch H., Scheurich P., Seliger B., Ucer U., Vehmeyer K., Nagel G. A. Differential gamma-interferon response of human colon carcinoma cells: inhibition of proliferation and modulation of immunogenicity as independent effects of gamma-interferon on tumor cell growth. Cancer Res. 1985 Aug;45(8):3503–3509. [PubMed] [Google Scholar]
  23. 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]
  24. 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]
  25. Scahill S. J., Devos R., Van der Heyden J., Fiers W. Expression and characterization of the product of a human immune interferon cDNA gene in Chinese hamster ovary cells. Proc Natl Acad Sci U S A. 1983 Aug;80(15):4654–4658. doi: 10.1073/pnas.80.15.4654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Scher M. G., Beller D. I., Unanue E. R. Demonstration of a soluble mediator that induces exudates rich in Ia-positive macrophages. J Exp Med. 1980 Dec 1;152(6):1684–1698. doi: 10.1084/jem.152.6.1684. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Snyder D. S., Beller D. I., Unanue E. R. Prostaglandins modulate macrophage Ia expression. Nature. 1982 Sep 9;299(5879):163–165. doi: 10.1038/299163a0. [DOI] [PubMed] [Google Scholar]
  28. Snyder D. S., Unanue E. R. Corticosteroids inhibit murine macrophage Ia expression and interleukin 1 production. J Immunol. 1982 Nov;129(5):1803–1805. [PubMed] [Google Scholar]
  29. Steeg P. S., Moore R. N., Johnson H. M., Oppenheim J. J. Regulation of murine macrophage Ia antigen expression by a lymphokine with immune interferon activity. J Exp Med. 1982 Dec 1;156(6):1780–1793. doi: 10.1084/jem.156.6.1780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Steeg P. S., Moore R. N., Oppenheim J. J. Regulation of murine macrophage Ia-antigen expression by products of activated spleen cells. J Exp Med. 1980 Dec 1;152(6):1734–1744. doi: 10.1084/jem.152.6.1734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Steinman R. M., Nogueira N., Witmer M. D., Tydings J. D., Mellman I. S. Lymphokine enhances the expression and synthesis of Ia antigens on cultured mouse peritoneal macrophages. J Exp Med. 1980 Nov 1;152(5):1248–1261. doi: 10.1084/jem.152.5.1248. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Sztein M. B., Steeg P. S., Johnson H. M., Oppenheim J. J. Regulation of human peripheral blood monocyte DR antigen expression in vitro by lymphokines and recombinant interferons. J Clin Invest. 1984 Feb;73(2):556–565. doi: 10.1172/JCI111243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Walker E. B., Maino V., Sanchez-Lanier M., Warner N., Stewart C. Murine gamma interferon activates the release of a macrophage-derived Ia-inducing factor that transfers Ia inductive capacity. J Exp Med. 1984 May 1;159(5):1532–1547. doi: 10.1084/jem.159.5.1532. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Wallach D., Fellous M., Revel M. Preferential effect of gamma interferon on the synthesis of HLA antigens and their mRNAs in human cells. Nature. 1982 Oct 28;299(5886):833–836. doi: 10.1038/299833a0. [DOI] [PubMed] [Google Scholar]
  35. Wong G. H., Bartlett P. F., Clark-Lewis I., Battye F., Schrader J. W. Inducible expression of H-2 and Ia antigens on brain cells. Nature. 1984 Aug 23;310(5979):688–691. doi: 10.1038/310688a0. [DOI] [PubMed] [Google Scholar]
  36. 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]

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

RESOURCES