LaFlam Taylor N, Seumois Grégory, Miller Corey N, Lwin Wint, Fasano Kayla J, Waterfield Michael, Proekt Irina, Vijayanand Pandurangan, Anderson Mark S
Diabetes Center, University of California, San Francisco, San Francisco, CA 94143.
La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037.
J Exp Med. 2015 Nov 16;212(12):1993-2002. doi: 10.1084/jem.20151069. Epub 2015 Nov 2.
Thymic central tolerance is essential to preventing autoimmunity. In medullary thymic epithelial cells (mTECs), the Autoimmune regulator (Aire) gene plays an essential role in this process by driving the expression of a diverse set of tissue-specific antigens (TSAs), which are presented and help tolerize self-reactive thymocytes. Interestingly, Aire has a highly tissue-restricted pattern of expression, with only mTECs and peripheral extrathymic Aire-expressing cells (eTACs) known to express detectable levels in adults. Despite this high level of tissue specificity, the cis-regulatory elements that control Aire expression have remained obscure. Here, we identify a highly conserved noncoding DNA element that is essential for Aire expression. This element shows enrichment of enhancer-associated histone marks in mTECs and also has characteristics of being an NF-κB-responsive element. Finally, we find that this element is essential for Aire expression in vivo and necessary to prevent spontaneous autoimmunity, reflecting the importance of this regulatory DNA element in promoting immune tolerance.
胸腺中枢耐受对于预防自身免疫至关重要。在髓质胸腺上皮细胞（mTEC）中，自身免疫调节因子（Aire）基因通过驱动多种组织特异性抗原（TSA）的表达在这一过程中发挥关键作用，这些抗原被呈递并有助于使自身反应性胸腺细胞产生耐受。有趣的是，Aire具有高度组织限制性的表达模式，在成体中仅髓质胸腺上皮细胞和外周胸腺外Aire表达细胞（eTAC）已知可表达可检测水平。尽管具有如此高水平的组织特异性，但控制Aire表达的顺式调控元件仍不清楚。在此，我们鉴定出一个对Aire表达至关重要的高度保守的非编码DNA元件。该元件在mTEC中显示出增强子相关组蛋白标记的富集，并且还具有NF-κB反应元件的特征。最后，我们发现该元件对于体内Aire表达至关重要，并且对于预防自发性自身免疫是必需的，这反映了这种调控DNA元件在促进免疫耐受中的重要性。
