T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17.
T-bet negatively regulates autoimmune myocarditis by suppressing local production of interleukin 17.
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DOI：
10.1084/jem.20052222
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发表时间：
2006-08-07
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实验性自身免疫性心肌炎（EAM）出现在感染性心脏病之后，感染性心脏病是人类扩张型心肌病最常见的原因。在这里，我们报告了缺乏T-bet（辅助性T细胞（Th）1分化和干扰素(IFN)-γ产生所需的T-box转录因子）的小鼠，与T-bet - / -对照小鼠相比，发生严重的自身免疫性心脏病。在T-bet−/−IL-4−/−和T-bet−/−IL-4Rα−/−小鼠以及心脏特异性Th1和Th2细胞系的转移中进行的实验表明，自身免疫性心脏病的发展独立于Th1或Th2极化。对T-bet−/−IL- 12r - β1−/−和T-bet−/−IL-12p35−/−小鼠的分析发现，白细胞介素(IL)-23在EAM发病机制中起关键作用。此外，T-bet - / -小鼠心脏浸润淋巴细胞产生il -23依赖性细胞因子IL-17显著增加，体内IL-17缺失显著降低了T-bet - / -小鼠EAM的严重程度。浸润心脏的T-bet - / - CD8+而非CD8 - T细胞分泌IFN-γ，抑制IL-17的产生并防止严重的EAM。相反，T-bet−/−CD8+淋巴细胞完全丧失了在心脏内释放IFN-γ的能力。总之，这些数据表明，严重的il -17介导的EAM可以在没有T-bet的情况下发生，T-bet可以通过控制发炎靶器官中的非特异性CD8+ T细胞旁观者功能来调节自身免疫。
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.