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Autoimmunity to DNA and Nucleosomes in Binary Tetracycline-Regulated Polyomavirus T-Ag Transgenic Mice¹

Signy Bendiksen^2,*, Marijke Van Ghelue^2,, Thomas Winkler, Ugo Moens^* and Ole Petter Rekvig^3,*,

^* Department of Biochemistry, Institute of Medical Biology, Faculty of Medicine, University of Tromsø, N-9037 Tromsø, Department of Medical Genetics, University Hospital Northern Norway, N-9038 Tromsø, Department of Genetics, Hematopoiesis Unit, Nikolaus Fiebiger Center for Molecular Medicine, University of Erlangen-Nurnberg, 91054 Erlangen, Germany, Department of Rheumatology, University Hospital Northern Norway, N-9038 Tromsø, Norway

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.

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