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

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)-γ production, develop severe autoimmune heart disease compared to T-bet (−/−) control mice. Experiments in T-bet (−/−) IL-4(−/−) and T-bet (−/−) IL-4Rα(−/−) 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-12Rβ1(−/−) 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-γ, which inhibits IL-17 production and protects against severe EAM. In contrast, T-bet (−/−) CD8(+) lymphocytes completely lost their capacity to release IFN-γ 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.