Alterations of the medullary epithelial compartment in the Aire-deficient thymus: implications for programs of thymic epithelial differentiation.
Alterations of the medullary epithelial compartment in the Aire-deficient thymus: implications for programs of thymic epithelial differentiation.
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DOI：
10.4049/jimmunol.181.8.5225
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发表时间：
2008-10-15
期刊：
影响因子：
--
通讯作者：
Farr AG
中科院分区：
文献类型：
--
作者：
Dooley J;Erickson M;Farr AG
一种广泛存在的胸腺上皮细胞分化模型是基于角蛋白的表达模式，其中K8+K5+祖细胞分化为K8+K5/K14−皮质胸腺上皮，而延髓胸腺上皮为K8−K5+K14+。P63基因缺陷小鼠的胸腺表型表明，p63是TE分化近端阶段的重要调节因子。在这项研究中，我们研究了WT和Aire缺陷胸腺的胸腺髓室的几个特征，试图将Aire的促凋亡活性与TE分化的这些不同角度相结合。本文描述的角蛋白和p63的表达模式很难与表达K8−K14+表型的有丝分裂后的MTEC相一致，提示反映其他上皮组织分化程序的p63和角蛋白的表达模式为修订TE分化模型提供了有用的框架。Aire−/−间隔室的改变包括p63表达减少，mTEC表达截短Aire蛋白的频率增加，角蛋白表达模式和上皮形态发生变化。这些数据表明，Aire介导的细胞凋亡的细胞靶点是尚未完成其末端分化程序的有丝分裂后的MTEC。根据这一观点，在AIRE+/+胸腺中观察到的少量球形K8+K14−/low MTEC，以及在AIRE−/−胸腺髓质中显著扩张的小群，代表终末期、终末分化的MTEC。这些依赖于Aire的MTEC间隔室的改变表明，Aire的活性在MTEC的分化过程中并不是中性的。
A widely held model of thymic epithelial differentiation is based on patterns of keratin expression, where a K8+K5+ progenitor gives rise to K8+K5/K14− cortical thymic epithelium (CTEC), and medullary thymic epithelium (MTEC) is K8−K5+K14+. The thymic phenotype of p63-deficient mice indicates that p63 is an important regulator of proximal stages of TE differentiation. In this study we have examined several features of the thymic medullary compartment in WT and Aire-deficient thymi in an effort to integrate the pro-apoptotic activity of Aire with these different perspectives of TE differentiation. Patterns of keratin and p63 expression by MTEC described here are difficult to reconcile with postmitotic MTEC that express a K8−K14+ phenotype and suggest that the patterns of p63 and keratin expression reflecting differentiation programs of other epithelial tissues provide a useful framework for revising models of TE differentiation. Alterations of the Aire−/− MTEC compartment included reduced expression of p63, increased frequency of MTEC expressing truncated Aire protein, and shifts in the pattern of keratin expression and epithelial morphology. These data suggest a scenario where cellular targets of Aire-mediated apoptosis are postmitotic MTEC that have not yet completed their terminal differentiation program. According to this view, the minor population of globular K8+K14−/low MTEC observed in the Aire+/+ thymus and that are significantly expanded in the Aire−/− thymic medulla represent end-stage, terminally differentiated MTEC. These Aire-dependent alterations of the MTEC compartment suggest that the activity of Aire is not neutral with respect to the program of MTEC differentiation.
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DOI：
10.1084/jem.20070795
发表时间：
2007-10-29
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Gray D;Abramson J;Benoist C;Mathis D
通讯作者：
Mathis D
DOI：
10.1073/pnas.77.7.4113
发表时间：
1980-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
BRULET, P;BABINET, C;JACOB, F
通讯作者：
JACOB, F
影响因子：
24.3
作者：
Elssner, A;Jaumann, F;Vogelmeier, C
通讯作者：
Vogelmeier, C
影响因子：
56.9
作者：
Anderson, MS;Venanzi, ES;Mathis, D
通讯作者：
Mathis, D
影响因子：
30.5
作者：
Derbinski, J;Schulte, A;Klein, L
通讯作者：
Klein, L