Thymic epithelial cell-specific deletion of Jmjd6 reduces Aire protein expression and exacerbates disease development in a mouse model of autoimmune diabetes.
Thymic epithelial cell-specific deletion of Jmjd6 reduces Aire protein expression and exacerbates disease development in a mouse model of autoimmune diabetes.
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DOI：
10.1016/j.bbrc.2017.05.113
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发表时间：
2017-07
影响因子：
3.1
通讯作者：
T. Yanagihara;Takahiro Tomino;T. Uruno;Y. Fukui
中科院分区：
文献类型：
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作者：
T. Yanagihara;Takahiro Tomino;T. Uruno;Y. Fukui
胸腺上皮细胞(TECs)建立空间上不同的微环境，在这个微环境中，发育中的T细胞被选择成熟或死亡。髓质TEC的一个独特特性是它们表达数千种组织限制性自身抗原，这些抗原在很大程度上受转录调控因子Aire的控制。我们以前发现Jmjd6是一种赖氨酰羟基酶，用于剪接调节蛋白，对Aire蛋白的表达是重要的，将Jmjd6缺陷的胸腺基质移植到裸鼠体内会导致多器官自身免疫。在此，我们报道了TEC特异的Jmjd6基因缺失会加剧小鼠自身免疫性糖尿病的发展，该模型既表达大鼠胰岛素基因启动子控制下的卵白蛋白(OVA)，又表达与主要组织相容性复合体I类Kb分子结合的OVA多肽的OT-I T细胞受体。我们发现，在缺乏Jmjd6的情况下，mTECs中Aire蛋白的表达减少，并保留了Aire转录产物中的内含子2。因此，我们的结果证明了Jmjd6在更具生理学意义的环境中建立免疫耐受的重要性。
Thymic epithelial cells (TECs) establish spatially distinct microenvironments in which developing T cells are selected to mature or die. A unique property of medullary TECs is their expression of thousands of tissue-restricted self-antigens that is largely under the control of the transcriptional regulator Aire. We previously showed that Jmjd6, a lysyl hydroxylase for splicing regulatory proteins, is important for Aire protein expression and that transplantation of Jmjd6-deficient thymic stroma into athymic nude mice resulted in multiorgan autoimmunity. Here we report that TEC-specific deletion ofJmjd6exacerbates development of autoimmune diabetes in a mouse model, which express both ovalbumin (OVA) under the control of the rat insulin gene promoter and OT-I T cell receptor specific for OVA peptide bound to major histocompatibility complex class I Kbmolecules. We found that Aire protein expression in mTECs was reduced in the absence of Jmjd6, with retention of intron 2 inAiretranscripts. Our results thus demonstrate the importance of Jmjd6 in establishment of immunological tolerance in a more physiological setting.