Yano Masashi, Kuroda Noriyuki, Han Hongwei, Meguro-Horike Makiko, Nishikawa Yumiko, Kiyonari Hiroshi, Maemura Kentaro, Yanagawa Yuchio, Obata Kunihiko, Takahashi Satoru, Ikawa Tomokatsu, Satoh Rumi, Kawamoto Hiroshi, Mouri Yasuhiro, Matsumoto Mitsuru
Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima, Japan.
J Exp Med. 2008 Nov 24;205(12):2827-38. doi: 10.1084/jem.20080046. Epub 2008 Nov 17.
The roles of autoimmune regulator (Aire) in the expression of the diverse arrays of tissue-restricted antigen (TRA) genes from thymic epithelial cells in the medulla (medullary thymic epithelial cells [mTECs]) and in organization of the thymic microenvironment are enigmatic. We approached this issue by creating a mouse strain in which the coding sequence of green fluorescent protein (GFP) was inserted into the Aire locus in a manner allowing concomitant disruption of functional Aire protein expression. We found that Aire(+) (i.e., GFP(+)) mTECs were the major cell types responsible for the expression of Aire-dependent TRA genes such as insulin 2 and salivary protein 1, whereas Aire-independent TRA genes such as C-reactive protein and glutamate decarboxylase 67 were expressed from both Aire(+) and Aire(-) mTECs. Remarkably, absence of Aire from mTECs caused morphological changes together with altered distribution of mTECs committed to Aire expression. Furthermore, we found that the numbers of mTECs that express involucrin, a marker for terminal epidermal differentiation, were reduced in Aire-deficient mouse thymus, which was associated with nearly an absence of Hassall's corpuscle-like structures in the medulla. Our results suggest that Aire controls the differentiation program of mTECs, thereby organizing the global mTEC integrity that enables TRA expression from terminally differentiated mTECs in the thymic microenvironment.
自身免疫调节因子（Aire）在髓质胸腺上皮细胞（mTECs）中组织限制性抗原（TRA）基因的多样表达以及胸腺微环境的组织构建中的作用尚不明确。我们通过构建一种小鼠品系来解决这个问题，在该品系中，绿色荧光蛋白（GFP）的编码序列以一种能同时破坏功能性Aire蛋白表达的方式插入到Aire基因座中。我们发现，Aire(+)（即GFP(+)）mTECs是负责表达依赖Aire的TRA基因（如胰岛素2和唾液蛋白1）的主要细胞类型，而不依赖Aire的TRA基因（如C反应蛋白和谷氨酸脱羧酶67）在Aire(+)和Aire(-) mTECs中均有表达。值得注意的是，mTECs中缺乏Aire会导致形态变化以及致力于Aire表达的mTECs分布改变。此外，我们发现，在Aire缺陷小鼠的胸腺中，表达终末表皮分化标志物兜甲蛋白的mTECs数量减少，这与髓质中几乎不存在哈氏小体样结构有关。我们的结果表明，Aire控制mTECs的分化程序，从而构建整体的mTECs完整性，使胸腺微环境中终末分化的mTECs能够表达TRA。
