The Journal of Experimental Medicine
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Published online 27 January 2003 doi:10.1084/jem.20021788
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© Rockefeller University Press, 0022-1007/2003/2/323 $5.00
The Journal of Experimental Medicine, Volume 197, Number 3, 323-331

Activation of Dendritic Cells through the Interleukin 1 Receptor 1 Is Critical for the Induction of Autoimmune Myocarditis

Urs Eriksson1,2, Michael O. Kurrer3, Ivo Sonderegger5, Giandomenica Iezzi5, Anna Tafuri2, Lukas Hunziker1, Shinobu Suzuki2, Kurt Bachmaier2,4, Roland M. Bingisser1, Josef M. Penninger2,4 and Manfred Kopf5

1 Medicine A, University Hospital, CH-4031 Basel, Switzerland
2 University Health Network, Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
3 Department of Pathology, University Hospital, CH-8091 Zurich, Switzerland
4 IMBA, Institute for Molecular Biotechnology of the Austrian Academy of Sciences, A-1030 Vienna, Austria
5 Molecular Biomedicine, Swiss Federal Institute of Technology, CH-8952 Zurich, Switzerland

Dilated cardiomyopathy, resulting from myocarditis, is the most common cause of heart failure in young patients. We here show that interleukin (IL)-1 receptor type 1–deficient (IL-1R1-/-) mice are protected from development of autoimmune myocarditis after immunization with {alpha}-myosin-peptide(614–629). CD4+ T cells from immunized IL-1R1-/- mice proliferated poorly and failed to transfer disease after injection into naive severe combined immunodeficiency (SCID) mice. In vitro stimulation experiments suggested that the function of IL-1R1-/-CD4+ T cells was not intrinsically defect, but their activation by dendritic cells was impaired in IL-1R1-/- mice. Accordingly, production of tumor necrosis factor (TNF)-{alpha}, IL-1, IL-6, and IL-12p70 was reduced in dendritic cells lacking the IL-1 receptor type 1. In fact, injection of immature, antigen-loaded IL-1R1+/+ but not IL-1R1-/- dendritic cells into IL-1R1-/- mice fully restored disease susceptibility by rendering IL-1R1-/- CD4+ T cells pathogenic. Thus, IL-1R1 triggering is required for efficient activation of dendritic cells, which is in turn a prerequisite for induction of autoreactive CD4+ T cells and autoimmunity.

Key Words: dendritic cells • interleukin 1 • interleukin 1 receptor type 1 • autoimmunity • myocarditis


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