Skip to main content
NCBI home page
Immunology logoLink to Immunology
. 1997 Jul;91(3):421–429. doi: 10.1046/j.1365-2567.1997.00258.x

Regulation of HLA class I and II expression by interferons and influenza A virus in human peripheral blood mononuclear cells.

P Keskinen 1, T Ronni 1, S Matikainen 1, A Lehtonen 1, I Julkunen 1
PMCID: PMC1364012  PMID: 9301532

Abstract

HLA class I and II molecules play a central role in regulating host immune responses against microbial infections because they present foreign antigens to CD8+ and CD4+ T lymphocytes, respectively. Many cytokines, especially interferons (IFN), are known to upregulate human leucocyte antigen (HLA) class I and II gene expression, but the kinetics, expression levels and viral regulation of HLA genes in primary human cells have not been well documented. Stimulation of peripheral blood mononuclear cells (PBMC) with IFN-alpha and IFN-gamma resulted in a 1.5- to twofold increase in HLA class I and beta 2-microglobulin expression in lymphocytes and monocytes. Lymphocytes did not express any detectable HLA class II either basally or after IFN induction. In monocytes, instead, a high basal class II expression was found and it was further induced by IFN-alpha (up to twofold) and especially by IFN-gamma (up to fivefold). In granulocyte-macrophage colony-stimulating factor (GM-CSF) differentiated human macrophages, basal HLA class I and II protein expression levels were high but IFN-gamma stimulation was able to further enhance their expression. Accordingly, class I and II mRNA expression was elevated by IFN-gamma, whereas IFN-alpha practically had no effect on HLA class I mRNA levels. Influenza A virus infection of macrophages resulted in temporary increases in HLA class I, beta 2-microglobulin and class II antigen expression. Neutralization of virus-induced IFN production by antibodies against type I and II IFNs prevented the virus-induced upregulation of HLA antigens. At late times of infection, as analysed by steady-state mRNA expression, both HLA class I and II mRNA were strongly reduced. These results suggest that IFNs are important regulators of HLA genes and responsible for a temporary increase in HLA antigen expression during influenza A virus infection.

Full text

PDF
421

Images in this article

426Figure 3
on p.426
427Figure 4
on p.427
428Figure 6
on p.428

Selected References

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

  1. Aebi M., Fäh J., Hurt N., Samuel C. E., Thomis D., Bazzigher L., Pavlovic J., Haller O., Staeheli P. cDNA structures and regulation of two interferon-induced human Mx proteins. Mol Cell Biol. 1989 Nov;9(11):5062–5072. doi: 10.1128/mcb.9.11.5062. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Arnheiter H., Frese M., Kambadur R., Meier E., Haller O. Mx transgenic mice--animal models of health. Curr Top Microbiol Immunol. 1996;206:119–147. doi: 10.1007/978-3-642-85208-4_8. [DOI] [PubMed] [Google Scholar]
  3. Bjorkman P. J., Parham P. Structure, function, and diversity of class I major histocompatibility complex molecules. Annu Rev Biochem. 1990;59:253–288. doi: 10.1146/annurev.bi.59.070190.001345. [DOI] [PubMed] [Google Scholar]
  4. Burns L. J., Waring J. F., Reuter J. J., Stinski M. F., Ginder G. D. Only the HLA class I gene minimal promoter elements are required for transactivation by human cytomegalovirus immediate early genes. Blood. 1993 Mar 15;81(6):1558–1566. [PubMed] [Google Scholar]
  5. Cantell K., Hirvonen S., Kauppinen H. L., Myllylä G. Production of interferon in human leukocytes from normal donors with the use of Sendai virus. Methods Enzymol. 1981;78(Pt A):29–38. doi: 10.1016/0076-6879(81)78094-7. [DOI] [PubMed] [Google Scholar]
  6. David-Watine B., Israël A., Kourilsky P. The regulation and expression of MHC class I genes. Immunol Today. 1990 Aug;11(8):286–292. doi: 10.1016/0167-5699(90)90114-o. [DOI] [PubMed] [Google Scholar]
  7. Dhib-Jalbut S. S., Cowan E. P. Direct evidence that interferon-beta mediates enhanced HLA-class I expression in measles virus-infected cells. J Immunol. 1993 Dec 1;151(11):6248–6258. [PubMed] [Google Scholar]
  8. Drew P. D., Lonergan M., Goldstein M. E., Lampson L. A., Ozato K., McFarlin D. E. Regulation of MHC class I and beta 2-microglobulin gene expression in human neuronal cells. Factor binding to conserved cis-acting regulatory sequences correlates with expression of the genes. J Immunol. 1993 Apr 15;150(8 Pt 1):3300–3310. [PubMed] [Google Scholar]
  9. Glimcher L. H., Kara C. J. Sequences and factors: a guide to MHC class-II transcription. Annu Rev Immunol. 1992;10:13–49. doi: 10.1146/annurev.iy.10.040192.000305. [DOI] [PubMed] [Google Scholar]
  10. Goetschy J. F., Zeller H., Content J., Horisberger M. A. Regulation of the interferon-inducible IFI-78K gene, the human equivalent of the murine Mx gene, by interferons, double-stranded RNA, certain cytokines, and viruses. J Virol. 1989 Jun;63(6):2616–2622. doi: 10.1128/jvi.63.6.2616-2622.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Gong J. H., Sprenger H., Hinder F., Bender A., Schmidt A., Horch S., Nain M., Gemsa D. Influenza A virus infection of macrophages. Enhanced tumor necrosis factor-alpha (TNF-alpha) gene expression and lipopolysaccharide-triggered TNF-alpha release. J Immunol. 1991 Nov 15;147(10):3507–3513. [PubMed] [Google Scholar]
  12. Johnson D. R., Pober J. S. HLA class I heavy-chain gene promoter elements mediating synergy between tumor necrosis factor and interferons. Mol Cell Biol. 1994 Feb;14(2):1322–1332. doi: 10.1128/mcb.14.2.1322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  14. Mach B., Steimle V., Martinez-Soria E., Reith W. Regulation of MHC class II genes: lessons from a disease. Annu Rev Immunol. 1996;14:301–331. doi: 10.1146/annurev.immunol.14.1.301. [DOI] [PubMed] [Google Scholar]
  15. Matikainen S., Ronni T., Hurme M., Pine R., Julkunen I. Retinoic acid activates interferon regulatory factor-1 gene expression in myeloid cells. Blood. 1996 Jul 1;88(1):114–123. [PubMed] [Google Scholar]
  16. Maudsley D. J., Pound J. D. Modulation of MHC antigen expression by viruses and oncogenes. Immunol Today. 1991 Dec;12(12):429–431. doi: 10.1016/0167-5699(91)90013-J. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Miyamoto M., Fujita T., Kimura Y., Maruyama M., Harada H., Sudo Y., Miyata T., Taniguchi T. Regulated expression of a gene encoding a nuclear factor, IRF-1, that specifically binds to IFN-beta gene regulatory elements. Cell. 1988 Sep 9;54(6):903–913. doi: 10.1016/s0092-8674(88)91307-4. [DOI] [PubMed] [Google Scholar]
  18. Mogensen K. E., Pyhälä L., Cantell K. Raising antibodies to human leukocyte interferon. Acta Pathol Microbiol Scand B. 1975 Oct;83(5):443–450. doi: 10.1111/j.1699-0463.1975.tb00123.x. [DOI] [PubMed] [Google Scholar]
  19. Nain M., Hinder F., Gong J. H., Schmidt A., Bender A., Sprenger H., Gemsa D. Tumor necrosis factor-alpha production of influenza A virus-infected macrophages and potentiating effect of lipopolysaccharides. J Immunol. 1990 Sep 15;145(6):1921–1928. [PubMed] [Google Scholar]
  20. Ponte P., Ng S. Y., Engel J., Gunning P., Kedes L. Evolutionary conservation in the untranslated regions of actin mRNAs: DNA sequence of a human beta-actin cDNA. Nucleic Acids Res. 1984 Feb 10;12(3):1687–1696. doi: 10.1093/nar/12.3.1687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Roberts N. J., Jr, Douglas R. G., Jr, Simons R. M., Diamond M. E. Virus-induced interferon production by human macrophages. J Immunol. 1979 Jul;123(1):365–369. [PubMed] [Google Scholar]
  22. Ronni T., Matikainen S., Sareneva T., Melén K., Pirhonen J., Keskinen P., Julkunen I. Regulation of IFN-alpha/beta, MxA, 2',5'-oligoadenylate synthetase, and HLA gene expression in influenza A-infected human lung epithelial cells. J Immunol. 1997 Mar 1;158(5):2363–2374. [PubMed] [Google Scholar]
  23. Ronni T., Melén K., Malygin A., Julkunen I. Control of IFN-inducible MxA gene expression in human cells. J Immunol. 1993 Mar 1;150(5):1715–1726. [PubMed] [Google Scholar]
  24. Ronni T., Sareneva T., Pirhonen J., Julkunen I. Activation of IFN-alpha, IFN-gamma, MxA, and IFN regulatory factor 1 genes in influenza A virus-infected human peripheral blood mononuclear cells. J Immunol. 1995 Mar 15;154(6):2764–2774. [PubMed] [Google Scholar]
  25. Sen G. C., Ransohoff R. M. Interferon-induced antiviral actions and their regulation. Adv Virus Res. 1993;42:57–102. doi: 10.1016/s0065-3527(08)60083-4. [DOI] [PubMed] [Google Scholar]
  26. Spriggs M. K. One step ahead of the game: viral immunomodulatory molecules. Annu Rev Immunol. 1996;14:101–130. doi: 10.1146/annurev.immunol.14.1.101. [DOI] [PubMed] [Google Scholar]
  27. Watanabe Y., Jacob C. O. Regulation of MHC class II antigen expression. Opposing effects of tumor necrosis factor-alpha on IFN-gamma-induced HLA-DR and Ia expression depends on the maturation and differentiation stage of the cell. J Immunol. 1991 Feb 1;146(3):899–905. [PubMed] [Google Scholar]
  28. Yang Y., Xiang Z., Ertl H. C., Wilson J. M. Upregulation of class I major histocompatibility complex antigens by interferon gamma is necessary for T-cell-mediated elimination of recombinant adenovirus-infected hepatocytes in vivo. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7257–7261. doi: 10.1073/pnas.92.16.7257. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Immunology are provided here courtesy of British Society for Immunology

RESOURCES