Identification of embryonic precursor cells that differentiate into thymic epithelial cells expressing autoimmune regulator.
Identification of embryonic precursor cells that differentiate into thymic epithelial cells expressing autoimmune regulator.
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DOI：
10.1084/jem.20151780
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发表时间：
2016-07-25
期刊：
影响因子：
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通讯作者：
Akiyama T
中科院分区：
文献类型：
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作者：
Akiyama N;Takizawa N;Miyauchi M;Yanai H;Tateishi R;Shinzawa M;Yoshinaga R;Kurihara M;Demizu Y;Yasuda H;Yagi S;Wu G;Matsumoto M;Sakamoto R;Yoshida N;Penninger JM;Kobayashi Y;Inoue J;Akiyama T
髓质胸腺上皮细胞（mTEC）祖细胞通过一条途径分化为成熟的Aire + mTEC，该途径起始于RANK和LtβR通过非经典NF - κB的信号传导，随后是TRAF - 6驱动的成熟过程。
表达自身免疫调节因子（Aire）的髓质胸腺上皮细胞（mTEC）对于预防自身免疫的发生至关重要。然而，表达Aire的mTEC（Aire + mTEC）的分化过程尚不清楚。在此，我们描述了Aire + mTEC的新型胚胎前体细胞。我们通过监测核因子 - κB受体激活剂（RANK）的表达发现了Aire + mTEC的候选前体细胞（pMEC），RANK是Aire + mTEC分化所必需的。pMEC除了mTEC标记物UEA - 1配体和RANK外，还意外地表达皮质TEC分子，并在重组胸腺器官培养中分化为mTEC。将pMEC引入胚胎胸腺可使Aire + mTEC长期维持，并有效抑制由Aire + mTEC缺失诱导的自身免疫的发生。从机制上讲，pMEC通过肿瘤坏死因子受体相关因子6依赖的RANK信号分化为Aire + mTEC。此外，由RANK和淋巴毒素 - β受体信号触发的非经典核因子 - κB激活促进了从表现出较低RANK表达和较高CD24表达的祖细胞诱导pMEC。因此，我们的研究结果确定了Aire + mTEC分化过程中的两个新阶段。
mTEC progenitors differentiate to mature Aire+ mTECs through a pathway that initiates with RANK and LtβR signaling via the nonclassical NF-κB, followed by TRAF-6–driven maturation. Medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (Aire) are critical for preventing the onset of autoimmunity. However, the differentiation program of Aire-expressing mTECs (Aire+ mTECs) is unclear. Here, we describe novel embryonic precursors of Aire+ mTECs. We found the candidate precursors of Aire+ mTECs (pMECs) by monitoring the expression of receptor activator of nuclear factor-κB (RANK), which is required for Aire+ mTEC differentiation. pMECs unexpectedly expressed cortical TEC molecules in addition to the mTEC markers UEA-1 ligand and RANK and differentiated into mTECs in reaggregation thymic organ culture. Introduction of pMECs in the embryonic thymus permitted long-term maintenance of Aire+ mTECs and efficiently suppressed the onset of autoimmunity induced by Aire+ mTEC deficiency. Mechanistically, pMECs differentiated into Aire+ mTECs by tumor necrosis factor receptor-associated factor 6-dependent RANK signaling. Moreover, nonclassical nuclear factor-κB activation triggered by RANK and lymphotoxin-β receptor signaling promoted pMEC induction from progenitors exhibiting lower RANK expression and higher CD24 expression. Thus, our findings identified two novel stages in the differentiation program of Aire+ mTECs.