Autoimmunity to DNA and nucleosomes in binary tetracycline-regulated polyomavirus T-Ag transgenic mice.
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.
Bendiksen
Signy
S
Department of Biochemistry, Institute of Medical Biology, Faculty of Medicine, University of Tromsø, N-9037 Tromsø, Norway.
Van Ghelue
Marijke
M
Winkler
Thomas
T
Moens
Ugo
U
Rekvig
Ole Petter
OP
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis*; D000914:Antibodies, Viral / Q000096:biosynthesis; D017951:Antigen Presentation / Q000235:genetics; D000957:Antigens, Viral, Tumor / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D022482:Cytomegalovirus Vaccines / Q000008:administration & dosage / Q000276:immunology; D004279:DNA, Viral / Q000276:immunology*; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009707:Nucleosomes / Q000276:immunology*; D011120:Polyomavirus / Q000235:genetics / Q000276:immunology*; D013539:Simian virus 40 / Q000276:immunology; D013752:Tetracycline / Q000008:administration & dosage / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics
D000974:Antibodies, Antinuclear; D000914:Antibodies, Viral; D000957:Antigens, Viral, Tumor; D022482:Cytomegalovirus Vaccines; D004279:DNA, Viral; D009707:Nucleosomes; D015534:Trans-Activators; D013752:Tetracycline