International Immunology Advance Access originally published online on December 16, 2005
International Immunology 2006 18(1):151-162; doi:10.1093/intimm/dxh357
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Experimental autoimmune encephalomyelitis in mice expressing the autoantigen MBP1–10 covalently bound to the MHC class II molecule I-Au
1 Department of Neuroimmunology, Max-Planck-Institute of Neurobiology, Am Klopferspitz 18, D-82152 Martinsried, Germany
2 Deutsches Krebsforschungszentrum DKFZ, Molekulare Immunologie, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
3 Fraunhofer Patentstelle für die Deutsche Forschung, Leonrodstrasse 68, 80636 München, Germany
4 Rhein Biotech GmbH, Eichsfelder Strasse 11, D-40595 Düsseldorf, Germany
5 Department of Pathology & Microbiology, University of Bristol, UK
Correspondence to: F. C. Kurschus; E-mail: kurschus{at}neuro.mpg.de
Most autoantigens implicated in multiple sclerosis (MS) are expressed not only in the central nervous system (CNS) but also in the thymus and the periphery. Nevertheless, these autoantigens might induce a strong autoimmune response leading to severe destruction within the CNS. To investigate the influence of a dominantly presented autoantigen on experimental autoimmune encephalomyelitis (EAE), we generated transgenic mice expressing the autoantigenic peptide MBP1–10 covalently bound to the MHC class II molecule I-Au. These mice were crossed either with B10.PL or with TCR-transgenic Tg4 mice, specific for the transgenic peptide–MHC combination. In double transgenic mice we found strong thymic deletion and residual peripheral T cells were refractory to antigen stimulation in vitro. Residual peripheral CD4+ T cells expressed activation markers and a high proportion was CD25 positive. Transfer of both CD25-negative and CD25-positive CD4+ T cells from double transgenic animals into B10.PL mice strongly inhibited the progression of EAE. Despite this thorough tolerance induction, some double transgenic mice developed severe signs of EAE after an extended period of time. Our data show that in the circumstances where autoantigenic priming persists, and where the number of antigen-specific T cells is high enough, autoimmunity may prevail over very potent tolerance-inducing mechanisms.
Keywords: autoimmunity, central nervous system, T lymphocytes, tolerance, transgenic mice, regulatory T cells