Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
J Exp Med. 2010 May 10;207(5):999-1013. doi: 10.1084/jem.20092384. Epub 2010 Apr 19.
Medullary thymic epithelial cells (mTECs) play an important role in T cell tolerance and prevention of autoimmunity. Mice deficient in expression of the signaling protein Sin exhibit exaggerated immune responses and multitissue inflammation. Here, we show that Sin is expressed in the thymic stroma, specifically in mTECs. Sin deficiency led to thymic stroma-dependent autoimmune manifestations shown by radiation chimeras and thymic transplants in nude mice, and associated with defective mTEC-mediated elimination of thymocytes in a T cell receptor transgenic model of negative selection. Lack of Sin expression correlated with a disorganized medullary architecture and fewer functionally mature mTECs under steady-state conditions. Additionally, Sin deficiency inhibited the expansion of mTECs in response to in vivo administration of keratinocyte growth factor (KGF). These results identify Sin as a novel regulator of mTEC development and T cell tolerance, and suggest that Sin is important for homeostatic maintenance of the medullary epithelium in the adult thymus.
髓质胸腺上皮细胞（mTECs）在 T 细胞耐受和预防自身免疫中发挥重要作用。缺乏信号蛋白 Sin 表达的小鼠表现出过度的免疫反应和多组织炎症。在这里，我们表明 Sin 在胸腺基质中表达，特别是在 mTECs 中。Sin 缺乏导致辐射嵌合体和裸鼠胸腺移植中依赖胸腺基质的自身免疫表现，并与 T 细胞受体转基因模型中阴性选择中 mTEC 介导的胸腺细胞消除缺陷相关。在稳态条件下，缺乏 Sin 表达与髓质结构紊乱和功能成熟 mTECs 减少相关。此外，Sin 缺乏抑制了体内给予角质细胞生长因子（KGF）后 mTEC 的扩增。这些结果表明 Sin 是 mTEC 发育和 T 细胞耐受的新型调节剂，并表明 Sin 对成年胸腺髓质上皮的稳态维持很重要。
