Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1995 Feb;95(2):486–492. doi: 10.1172/JCI117689

Sensitization to self (virus) antigen by in situ expression of murine interferon-gamma.

M S Lee 1, M von Herrath 1, H Reiser 1, M B Oldstone 1, N Sarvetnick 1
PMCID: PMC295495  PMID: 7860730

Abstract

Autoimmune disease results from inflammatory destruction of tissues by aberrant self-reactive lymphocytes. We studied the autoimmune potential of T lymphocytes immunologically ignorant of viral antigens acting as self antigens and whether the host defense molecule IFN-gamma could stimulate these cells to cytotoxic competency. For this purpose, we produced double transgenic mice expressing pancreatic IFN-gamma as well as lymphocytic choriomeningitis virus (LCMV) nucleoprotein (NP) or glycoprotein (GP) antigen. 100% of the NP+/IFN-gamma+ mice became diabetic before 2 mo of age, while none of the NP single transgenic littermates and only 10% of IFN-gamma single transgenic littermates did. Strikingly, NP+/IFN-gamma+ mice spontaneously developed cytotoxic T lymphocyte activity on LCMV-infected targets and vaccinia virus-NP-infected ones without prior LCMV infection but NP+/IFN-gamma- mice did not, which indicates specific sensitization to the viral antigen by IFN-gamma. These results suggest that lymphocytes ignorant of self antigens can be activated by IFN-gamma released after immunologic stimulation such as viral infection. This mechanism may account for the loss of apparent tolerance to self antigens in autoimmune diseases such as insulin-dependent diabetes mellitus.

Full text

PDF
486

Images in this article

488Image
on p.488
488Image
on p.488
490Image
on p.490
490Image
on p.490

Selected References

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

  1. Allison J., Malcolm L., Chosich N., Miller J. F. Inflammation but not autoimmunity occurs in transgenic mice expressing constitutive levels of interleukin-2 in islet beta cells. Eur J Immunol. 1992 May;22(5):1115–1121. doi: 10.1002/eji.1830220503. [DOI] [PubMed] [Google Scholar]
  2. Gajewski T. F., Fitch F. W. Anti-proliferative effect of IFN-gamma in immune regulation. I. IFN-gamma inhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones. J Immunol. 1988 Jun 15;140(12):4245–4252. [PubMed] [Google Scholar]
  3. Gu D., Lee M. S., Krahl T., Sarvetnick N. Transitional cells in the regenerating pancreas. Development. 1994 Jul;120(7):1873–1881. doi: 10.1242/dev.120.7.1873. [DOI] [PubMed] [Google Scholar]
  4. Gu D., Sarvetnick N. Epithelial cell proliferation and islet neogenesis in IFN-g transgenic mice. Development. 1993 May;118(1):33–46. doi: 10.1242/dev.118.1.33. [DOI] [PubMed] [Google Scholar]
  5. Guerder S., Picarella D. E., Linsley P. S., Flavell R. A. Costimulator B7-1 confers antigen-presenting-cell function to parenchymal tissue and in conjunction with tumor necrosis factor alpha leads to autoimmunity in transgenic mice. Proc Natl Acad Sci U S A. 1994 May 24;91(11):5138–5142. doi: 10.1073/pnas.91.11.5138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Harding F. A., Allison J. P. CD28-B7 interactions allow the induction of CD8+ cytotoxic T lymphocytes in the absence of exogenous help. J Exp Med. 1993 Jun 1;177(6):1791–1796. doi: 10.1084/jem.177.6.1791. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Harlan D. M., Hengartner H., Huang M. L., Kang Y. H., Abe R., Moreadith R. W., Pircher H., Gray G. S., Ohashi P. S., Freeman G. J. Mice expressing both B7-1 and viral glycoprotein on pancreatic beta cells along with glycoprotein-specific transgenic T cells develop diabetes due to a breakdown of T-lymphocyte unresponsiveness. Proc Natl Acad Sci U S A. 1994 Apr 12;91(8):3137–3141. doi: 10.1073/pnas.91.8.3137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Harrison L. C., Honeyman M. C., DeAizpurua H. J., Schmidli R. S., Colman P. G., Tait B. D., Cram D. S. Inverse relation between humoral and cellular immunity to glutamic acid decarboxylase in subjects at risk of insulin-dependent diabetes. Lancet. 1993 May 29;341(8857):1365–1369. doi: 10.1016/0140-6736(93)90940-i. [DOI] [PubMed] [Google Scholar]
  9. Heath W. R., Allison J., Hoffmann M. W., Schönrich G., Hämmerling G., Arnold B., Miller J. F. Autoimmune diabetes as a consequence of locally produced interleukin-2. Nature. 1992 Oct 8;359(6395):547–549. doi: 10.1038/359547a0. [DOI] [PubMed] [Google Scholar]
  10. Higuchi Y., Herrera P., Muniesa P., Huarte J., Belin D., Ohashi P., Aichele P., Orci L., Vassalli J. D., Vassalli P. Expression of a tumor necrosis factor alpha transgene in murine pancreatic beta cells results in severe and permanent insulitis without evolution towards diabetes. J Exp Med. 1992 Dec 1;176(6):1719–1731. doi: 10.1084/jem.176.6.1719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Klavinskis L. S., Whitton J. L., Oldstone M. B. Molecularly engineered vaccine which expresses an immunodominant T-cell epitope induces cytotoxic T lymphocytes that confer protection from lethal virus infection. J Virol. 1989 Oct;63(10):4311–4316. doi: 10.1128/jvi.63.10.4311-4316.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Lee M. S., Wogensen L., Shizuru J., Oldstone M. B., Sarvetnick N. Pancreatic islet production of murine interleukin-10 does not inhibit immune-mediated tissue destruction. J Clin Invest. 1994 Mar;93(3):1332–1338. doi: 10.1172/JCI117092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Martin L., Mora-Worms M., Lucas C., Reynolds C., Stewart T. A. An evaluation of mechanisms by which tolerance to organ-specific antigens is lost using a transgenic mouse model. J Immunol. 1993 Feb 15;150(4):1234–1243. [PubMed] [Google Scholar]
  14. Ohashi P. S., Oehen S., Buerki K., Pircher H., Ohashi C. T., Odermatt B., Malissen B., Zinkernagel R. M., Hengartner H. Ablation of "tolerance" and induction of diabetes by virus infection in viral antigen transgenic mice. Cell. 1991 Apr 19;65(2):305–317. doi: 10.1016/0092-8674(91)90164-t. [DOI] [PubMed] [Google Scholar]
  15. Oldstone M. B., Nerenberg M., Southern P., Price J., Lewicki H. Virus infection triggers insulin-dependent diabetes mellitus in a transgenic model: role of anti-self (virus) immune response. Cell. 1991 Apr 19;65(2):319–331. doi: 10.1016/0092-8674(91)90165-u. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. 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]
  18. Sarvetnick N., Liggitt D., Pitts S. L., Hansen S. E., Stewart T. A. Insulin-dependent diabetes mellitus induced in transgenic mice by ectopic expression of class II MHC and interferon-gamma. Cell. 1988 Mar 11;52(5):773–782. doi: 10.1016/0092-8674(88)90414-X. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Sarvetnick N., Shizuru J., Liggitt D., Martin L., McIntyre B., Gregory A., Parslow T., Stewart T. Loss of pancreatic islet tolerance induced by beta-cell expression of interferon-gamma. Nature. 1990 Aug 30;346(6287):844–847. doi: 10.1038/346844a0. [DOI] [PubMed] [Google Scholar]
  20. Tisch R., Yang X. D., Singer S. M., Liblau R. S., Fugger L., McDevitt H. O. Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature. 1993 Nov 4;366(6450):72–75. doi: 10.1038/366072a0. [DOI] [PubMed] [Google Scholar]
  21. Whitton J. L., Southern P. J., Oldstone M. B. Analyses of the cytotoxic T lymphocyte responses to glycoprotein and nucleoprotein components of lymphocytic choriomeningitis virus. Virology. 1988 Feb;162(2):321–327. doi: 10.1016/0042-6822(88)90471-0. [DOI] [PubMed] [Google Scholar]
  22. von Herrath M. G., Allison J., Miller J. F., Oldstone M. B. Focal expression of interleukin-2 does not break unresponsiveness to "self" (viral) antigen expressed in beta cells but enhances development of autoimmune disease (diabetes) after initiation of an anti-self immune response. J Clin Invest. 1995 Feb;95(2):477–485. doi: 10.1172/JCI117688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. von Herrath M. G., Dockter J., Oldstone M. B. How virus induces a rapid or slow onset insulin-dependent diabetes mellitus in a transgenic model. Immunity. 1994 Jun;1(3):231–242. doi: 10.1016/1074-7613(94)90101-5. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES