The Journal of Experimental Medicine
Keystone Symposia
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Published online 31 July 2006 doi:10.1084/jem.20052222
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 8, 2009-2019
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ARTICLE

 T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17

Manu Rangachari1,2, Nora Mauermann3, René R. Marty3, Stephan Dirnhofer4, Michael O. Kurrer5, Vukoslav Komnenovic1, Josef M. Penninger1, and Urs Eriksson3

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)-{gamma} production, develop severe autoimmune heart disease compared to T-bet–/– control mice. Experiments in T-bet–/– IL-4–/– and T-bet–/– IL-4R{alpha}–/– 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-{gamma}, which inhibits IL-17 production and protects against severe EAM. In contrast, T-bet–/– CD8+ lymphocytes completely lost their capacity to release IFN-{gamma} 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-{alpha}, myosin {alpha} heavy chain; T reg, regulatory T.

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


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