title: T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17.
abstract: 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-4Ralpha-/- 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-12Rbeta1-/- 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.
authors.affiliation: Institute for Molecular Biotechnology of the Austrian Academy of Sciences, A-1030 Vienna, Austria.
authors.forename: Manu
authors.initials: M
authors.lastname: Rangachari
authors.forename: Nora
authors.initials: N
authors.lastname: Mauermann
authors.forename: René R
authors.initials: RR
authors.lastname: Marty
authors.forename: Stephan
authors.initials: S
authors.lastname: Dirnhofer
authors.forename: Michael O
authors.initials: MO
authors.lastname: Kurrer
authors.forename: Vukoslav
authors.initials: V
authors.lastname: Komnenovic
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Urs
authors.initials: U
authors.lastname: Eriksson
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000378:metabolism; D015551:Autoimmunity / Q000276:immunology; D001853:Bone Marrow; D017252:CD3 Complex / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D006801:Humans; D007114:Immunization; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000172:deficiency; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000096:biosynthesis; D008221:Lymphoid Tissue / Q000276:immunology; D051379:Mice; D016513:Mice, SCID; D009205:Myocarditis / Q000276:immunology* / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000473:pathology; D015375:Receptors, Interleukin-2 / Q000276:immunology; D020825:T-Box Domain Proteins; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology; D014157:Transcription Factors / Q000172:deficiency / Q000378:metabolism*; D000098815:T-bet Transcription Factor
chemical_list: D017252:CD3 Complex; D016207:Cytokines; C508840:IL23A protein, human; C508841:Il23a protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D015375:Receptors, Interleukin-2; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors