Aire-dependent alterations in medullary thymic epithelium indicate a role for Aire in thymic epithelial differentiation
Aire-dependent alterations in medullary thymic epithelium indicate a role for Aire in thymic epithelial differentiation
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DOI：
10.4049/jimmunol.178.5.3007
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发表时间：
2007-03-01
影响因子：
4.4
通讯作者：
Farr, Andrew G.
中科院分区：
文献类型：
--
作者：
Gillard, Geoffrey O.;Dooley, James;Farr, Andrew G.
胸腺上皮分化和Aire活性的流行观点认为，Aire在终末分化的胸腺髓质上皮细胞（MTECs）中的功能是去抑制结构组织限制性Ag的表达，包括胰腺内分泌激素。这些过程的另一种观点认为，Aire的功能是调节未成熟胸腺上皮细胞的分化，从而影响组织限制性Ag表达和负选择。在这项研究中，我们证明了Aire影响小鼠MTEC的几个方面，并为第二种模型提供支持。与祖细胞发育可塑性相关的转录因子Nanog、Oct4和Sox 2的表达依赖于Aire。同样。调节胰腺发育和胰腺激素表达的转录因子也由野生型MTEC以Aire依赖性方式表达。Aire缺陷型MTECs的转录谱改变伴随着髓质上皮区室的组织和组成的变化，包括由角蛋白（K）14表达定义的髓质区室减少，K5和K8表达模式改变，以及更突出的上皮囊肿。这些研究结果表明，Aire在MTEC分化和胸腺髓质区室组织的调节中起作用，并且与Aire在胸腺上皮分化中的作用相一致。
The prevalent view of thymic epithelial differentiation and Aire activity holds that Aire functions in terminally differentiated medullary thymic epithelial cells (MTECs) to derepress the expression of structural tissue-restricted Ags, including pancreatic endocrine hormones. An alternative view of these processes has proposed that Aire functions to regulate the differentiation of immature thymic epithelial cells, thereby affecting tissue-restricted Ag expression and negative selection. In this study, we demonstrate that Aire impacts several aspects of murine MTECs and provide support for this second model. Expression of transcription factors associated with developmental plasticity of progenitor cells, Nanog, Oct4, and Sox2, by MTECs was Aire dependent. Similarly. the transcription factors that regulate pancreatic development and the expression of pancreatic hormones are also expressed by wild-type MTECs in an Aire-dependent manner. The altered transcriptional profiles in Aire-deficient MTECs were accompanied by changes in the organization and composition of the medullary epithelial compartment, including a reduction in the medullary compartment defined by keratin (K) 14 expression, altered patterns of K5 and K8 expression, and more prominent epithelial cysts. These findings implicate Aire in the regulation of MTEC differentiation and the organization of the medullary thymic compartment and are compatible with a role for Aire in thymic epithelium differentiation.