Autoimmunity to DNA and Nucleosomes in Binary Tetracycline-Regulated Polyomavirus T-Ag Transgenic Mice

• Published in: The Journal of immunology (1950) 2004-12, Vol.173 (12), p.7630-7640
• Main Authors: Bendiksen, Signy, Van Ghelue, Marijke, Winkler, Thomas, Moens, Ugo, Rekvig, Ole Petter
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Antinuclear - biosynthesis; Antibodies, Viral - biosynthesis; Antigen Presentation - genetics; Antigens, Viral, Tumor - administration & dosage; Antigens, Viral, Tumor - biosynthesis; Antigens, Viral, Tumor - genetics; Antigens, Viral, Tumor - physiology; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - immunology; Cells, Cultured; Cytomegalovirus Vaccines - administration & dosage; Cytomegalovirus Vaccines - immunology; DNA, Viral - immunology; Lymphocyte Activation - genetics; Mice; Mice, Inbred BALB C; Mice, Transgenic; Nucleosomes - immunology; Polyomavirus; Polyomavirus - genetics; Polyomavirus - immunology; Simian virus 40; Simian virus 40 - immunology; Tetracycline - administration & dosage; Tetracycline - pharmacology; Trans-Activators - genetics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.173.12.7630

The mechanism(s) responsible for autoimmunity to DNA and nucleosomes in SLE is largely unknown. We have demonstrated that nucleosome-polyomavirus T-Ag complexes, formed in context of productive polyomavirus infection, activate dsDNA-specific B cells and nucleosome-specific CD4(+) T cells. To investigate whether de novo expressed T-Ag is able to terminate nucleosome-specific T cell tolerance and to maintain anti-dsDNA Ab production in nonautoimmune mice, we developed two binary transgenic mouse variants in which expression of SV40 large T-Ag is controlled by tetracycline, MUP tTA/T-Ag (tet-off), and CMV rtTA/T-Ag (tet-on) mice. Data demonstrate that MUP tTA/T-Ag mice, but not CMV rtTA/T-Ag mice, are tightly controlling T-Ag expression. In MUP tTA/T-Ag transgenic mice, postnatal T-Ag expression activated CD8(+) T cells but not DNA-specific B cells, while immunization with T-Ag and nucleosome-T-Ag-complexes before T-Ag expression resulted in elevated and remarkably stable titers of anti-T-Ag and anti-dsDNA Abs and activation of T-Ag-specific CD4(+) T cells. Immunization of nonexpressing MUP tTA/T-Ag mice resulted in transient anti-T-Ag and anti-dsDNA Abs. This system reveals that a de novo expressed DNA-binding quasi-autoantigen maintain anti-dsDNA Abs and CD4(+) T cell activation once initiated by immunization, demonstrating direct impact of a single in vivo expressed molecule on sustained autoimmunity to DNA and nucleosomes.