Phosphatase Wip1 Is Essential for the Maturation and Homeostasis of Medullary Thymic Epithelial Cells in Mice
Phosphatase Wip1 Is Essential for the Maturation and Homeostasis of Medullary Thymic Epithelial Cells in Mice
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DOI：
10.4049/jimmunol.1300363
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发表时间：
2013-09
期刊：
影响因子：
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通讯作者：
Lina Sun;Hongran Li;Haiying Luo;Lianjun Zhang;Xuelian Hu;Tao Yang;Chenming Sun;H. Chen;
中科院分区：
文献类型：
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作者：
Lina Sun;Hongran Li;Haiying Luo;Lianjun Zhang;Xuelian Hu;Tao Yang;Chenming Sun;H. Chen;
胸腺上皮细胞（TEC）是胸腺微环境中T细胞发育所必需的关键细胞类型。然而，控制TEC分化和活动的内在分子机制还不清楚。在这项研究中，我们发现，p53诱导的磷酸酶1（Wip 1）在小鼠中的缺陷选择性地导致严重的髓TEC（mTEC）的成熟缺陷的内在方式。Wip 1基因敲除（KO）小鼠在出生后阶段（而不是在胎儿阶段）具有减少的成熟上皮细胞粘附分子+荆豆凝集素-1（UEA-1）+mTEC，包括UEA-1+MHC II类高、UEA-1+ CD 80+、UEA-1+ CD 40+和UEA-1+Aire+细胞，但不减少皮质上皮细胞粘附分子+BP-1+ TEC的数量。Wip 1缺陷型mTEC表达较少的组织限制性Ag和UEA-1+外皮蛋白+终末分化细胞。动物模型，包括胎儿Wip 1缺陷胸腺组织移植到T细胞缺陷的裸鼠和重建致死照射Wip 1 KO小鼠受体与野生型骨髓细胞，也显示受损的mTEC组件Wip 1 KO胸腺，表明内在的调节作用Wip 1在mTEC成熟。此外，环磷酰胺处理后，成年Wip 1 KO小鼠的胸腺再生效率明显低于野生型小鼠。Wip 1缺陷导致mTECs中p38 MAPK活性升高。活化的p38 MAPK具有抑制mTECs上CD 40表达的能力。在胎儿胸腺器官培养系统中，Wip 1缺陷胸腺对CD 40 L的反应较差。因此，Wip 1通过限制p38 MAPK途径积极控制mTEC成熟、稳态和再生。
Thymic epithelial cells (TECs) are a key cell type in the thymic microenvironment essential for T cell development. However, intrinsic molecular mechanisms controlling TEC differentiation and activities are poorly defined. In this study, we found that deficiency of p53-induced phosphatase 1 (Wip1) in mice selectively caused severe medullary TEC (mTEC) maturation defects in an intrinsic manner. Wip1 knockout (KO) mice had decreased mature epithelial cell adhesion molecule+Ulex europaeus agglutinin-1 (UEA-1)+ mTECs, including UEA-1+MHC class IIhigh, UEA-1+CD80+, UEA-1+CD40+, and UEA-1+Aire+ cells, but not decreased numbers of cortical epithelial cell adhesion molecule+BP-1+ TECs, in the postnatal stage but not in the fetal stage. Wip1-deficient mTECs express fewer tissue-restricted Ags and UEA-1+involucrin+ terminal-differentiated cells. Animal models, including grafting fetal Wip1-deficient thymic tissue into T cell–deficient nude mice and reconstitution of lethally irradiated Wip1KO mouse recipients with wild-type bone marrow cells, also showed the impaired mTEC components in Wip1KO thymi, indicating the intrinsic regulatory role of Wip1 in mTEC maturation. Furthermore, thymus regeneration was significantly less efficient in adult Wip1KO mice than in wild-type mice after cyclophosphamide treatment. Wip1 deficiency resulted in elevated p38 MAPK activity in mTECs. Activated p38 MAPK has the ability to suppress CD40 expression on mTECs. Wip1-deficient thymi displayed poor response to CD40L in the fetal thymus organ culture system. Thus, Wip1 positively controls mTEC maturation, homeostasis, and regeneration through limiting the p38 MAPK pathway.