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¹ Institute for Molecular Biotechnology of the Austrian Academy of Sciences, A-1030 Vienna, Austria
² Graduate Programme in Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada
³ Department of Research and Department of Internal Medicine, Experimental Critical Care Medicine, and ⁴ Department of Pathology, University Hospital, CH-4031 Basel, Switzerland
⁵ Department of Pathology, University Hospital, CH-8091 Zürich, Switzerland

CORRESPONDENCE Urs Eriksson: ueriksson{at}uhbs.ch OR Josef M. Penninger: josef.penninger{at}imba.oeaw.ac.at

Experimental autoimmune myocarditis (EAM) appears after infectious heart disease, the most common cause of dilated cardiomyopathy in humans. Here we report that mice lacking T-bet, a T-box transcription factor required for T helper (Th)1 cell differentiation and interferon (IFN)- production, develop severe autoimmune heart disease compared to T-bet^–/– control mice. Experiments in T-bet^–/– IL-4^–/– and T-bet^–/– IL-4R^–/– mice, as well as transfer of heart-specific Th1 and Th2 cell lines, showed that autoimmune heart disease develops independently of Th1 or Th2 polarization. Analysis of T-bet^–/– IL-12Rß1^–/– and T-bet^–/– IL-12p35^–/– mice then identified interleukin (IL)-23 as critical for EAM pathogenesis. In addition, T-bet^–/– mice showed a marked increase in production of the IL-23–dependent cytokine IL-17 by heart-infiltrating lymphocytes, and in vivo IL-17 depletion markedly reduced EAM severity in T-bet^–/– mice. Heart-infiltrating T-bet^–/– CD8⁺ but not CD8^– T cells secrete IFN-, which inhibits IL-17 production and protects against severe EAM. In contrast, T-bet^–/– CD8⁺ lymphocytes completely lost their capacity to release IFN- within the heart. Collectively, these data show that severe IL-17–mediated EAM can develop in the absence of T-bet, and that T-bet can regulate autoimmunity via the control of nonspecific CD8⁺ T cell bystander functions in the inflamed target organ.

Abbreviations used: BMDC, bone marrow–derived DC; DCM, dilated cardiomyopathy; EAM, experimental autoimmune myocarditis; MyHC-, myosin heavy chain; T reg, regulatory T.

J.M. Penninger and U. Eriksson contributed equally to this work.

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