Autoreactive CD4 T cells that differentiate into pathogenic Th17 cells can trigger autoimmune diseases. Therefore, investigating the regulatory network that modulates Th17 differentiation may yield important therapeutic insights. miR-146a has emerged as a critical modulator of immune reactions, but its role in regulating autoreactive Th17 cells and organ-specific autoimmunity remains largely unknown. Here, we have reported that miR-146a-deficient mice developed more severe experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS). We bred miR-146a-deficient mice with 2D2 T cell receptor-Tg mice to generate 2D2 CD4 T cells that are deficient in miR-146a and specific for myelin oligodendrocyte glycoprotein (MOG), an autoantigen in the EAE model. miR-146a-deficient 2D2 T cells induced more severe EAE and were more prone to differentiate into Th17 cells. Microarray analysis revealed enhancements in IL-6- and IL-21-induced Th17 differentiation pathways in these T cells. Further study showed that miR-146a inhibited the production of autocrine IL-6 and IL-21 in 2D2 T cells, which in turn reduced their Th17 differentiation. Thus, our study identifies miR-146a as an important molecular brake that blocks the autocrine IL-6- and IL-21-induced Th17 differentiation pathways in autoreactive CD4 T cells, highlighting its potential as a therapeutic target for treating autoimmune diseases.

中文翻译：

---

miR-146a调节自身反应性Th17细胞分化并调节器官特异性自身免疫。

分化为致病性Th17细胞的自身反应性CD4 T细胞可引发自身免疫性疾病。因此，研究调节Th17分化的调控网络可能会产生重要的治疗见解。miR-146a已成为免疫反应的关键调节剂，但其在调节自身反应性Th17细胞和器官特异性自身免疫中的作用仍然未知。在这里，我们已经报道了miR-146a缺陷型小鼠发展了更为严重的实验性自身免疫性脑脊髓炎（EAE），这是一种人类多发性硬化症（MS）的动物模型。我们用2D2 T细胞受体-Tg小鼠饲养了miR-146a缺陷小鼠，以产生2D2 CD4 T细胞，该2D2 CD4 T细胞缺乏miR-146a，并且对EAE模型中的一种自身抗原髓磷脂少突胶质糖蛋白（MOG）具有特异性。缺乏miR-146a的2D2 T细胞诱导出更严重的EAE，并且更易于分化为Th17细胞。基因芯片分析显示这些T细胞中IL-6和IL-21诱导的Th17分化途径增强。进一步的研究表明，miR-146a抑制2D2 T细胞中自分泌IL-6和IL-21的产生，从而降低了它们的Th17分化。因此，我们的研究确定了miR-146a是一种重要的分子制动器，它可以阻断自身反应性CD4 T细胞中自分泌IL-6和IL-21诱导的Th17分化途径，突出了其作为治疗自身免疫性疾病的治疗靶标的潜力。进一步的研究表明，miR-146a抑制2D2 T细胞中自分泌IL-6和IL-21的产生，从而降低了它们的Th17分化。因此，我们的研究确定了miR-146a是一种重要的分子制动器，它可以阻断自身反应性CD4 T细胞中自分泌IL-6和IL-21诱导的Th17分化途径，突出了其作为治疗自身免疫性疾病的治疗靶标的潜力。进一步的研究表明，miR-146a抑制2D2 T细胞中自分泌IL-6和IL-21的产生，从而降低了它们的Th17分化。因此，我们的研究确定了miR-146a是一种重要的分子制动器，可阻断自身反应性CD4 T细胞中自分泌IL-6和IL-21诱导的Th17分化途径，从而突出了其作为治疗自身免疫性疾病的治疗靶标的潜力。