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Skin Inflammation Is Not Sufficient to Break Tolerance Induced against a Novel Antigen¹

Martin Holcmann^*, Patrizia Stoitzner, Barbara Drobits^*, Petra Luehrs^2,, Georg Stingl, Nikolaus Romani, Dieter Maurer and Maria Sibilia^3,*

*Institute for Cancer Research, Department of Medicine I, Medical University of Vienna, Borschkegasse 8a, Vienna, Austria; Department of Dermatology, Division of Immunology, Allergology, and Infectious Diseases, Medical University of Vienna, Währinger Gürtel 18-20, Vienna, Austria; and Department of Dermatology and Venereology, Innsbruck Medical University, Innsbruck, Austria

Depending on the cellular and molecular microenvironment, immune responses generated by skin-associated lymphoid tissues can lead to protective immunity against pathogens or to tolerance. In this study, we investigated immune responses to an Ag expressed de novo in adult skin under homeostatic conditions by generating transgenic mice producing the Ag Ova in a Cre-inducible manner in keratinocytes. Expression of Ova was induced in adult mice with a tamoxifen-inducible K5-CreER transgenic line. Although Ova was efficiently expressed by keratinocytes and presented by Langerhans cells after Cre-mediated transgene recombination, adult transgenic mice did not develop any obvious autoimmune disease symptoms like hair or weight loss. Ag-specific T cells were activated after Ova expression as indicated by up-regulation of CD44 and CD69. After in vitro restimulation Ova-specific T cells showed reduced IFN- production suggesting induction of tolerance after Ova expression in the skin. After transfer into Ova-expressing mice, naive OT-1 T cells transiently proliferated in skin-draining lymph nodes, infiltrated the skin but did not cause disease. Topical application of danger signals at the time of Ova induction did also not induce autoimmune disease. The unresponsiveness of Ag-specific T cells after induction of Ova expression could only be circumvented by simultaneous priming with CpG-matured, bone marrow-derived dendritic cells. Our data suggest that low amount of Ag expressed in the induction phase of the immune response results in tolerance even in the presence of danger signals and thereby helps to preserve homeostasis in the skin under normal and pathologic conditions.

³Address correspondence and reprint requests to Dr. Maria Sibilia, Borschkegasse 8a, Vienna, Austria. E-mail address: Maria.Sibilia{at}meduniwien.ac.at

¹ This project was supported by the Competence Center for Biomolecular Therapeutics (BMT) and the Austrian Science Fund FWF-P18782. M.S. acknowledges funding from the European Community Grant LSHC-CT-2006-03773, GEN-AU (Austromouse) GZ 200.147/1-VI/1/2006 and the FWF (Grants P18421, SFB-23-B13 and DK W1212). P.S. was supported by a Grant from Innsbruck Medical University (MFI no. 4510). B.D. is a recipient of a DOC-FORTE fellowship from the Austrian Academy of Sciences (ÖAW).

² Current address: Affiris, Campus Vienna Biocenter, Viehmarktgasse 2A, Vienna, Austria.