Alternative NF-κB signaling regulates mTEC differentiation from podoplanin-expressing presursors in the cortico-medullary junction
Alternative NF-κB signaling regulates mTEC differentiation from podoplanin-expressing presursors in the cortico-medullary junction
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DOI：
10.1002/eji.201545677
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发表时间：
2015-08-01
影响因子：
5.4
通讯作者：
Ludewig, Burkhard
中科院分区：
文献类型：
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作者：
Onder, Lucas;Nindl, Veronika;Ludewig, Burkhard
胸腺上皮形成专门的壁龛，使胸腺细胞分化。虽然髓质和皮质胸腺上皮细胞的共同上皮祖细胞(mTECs和cTECs)已经被很好地定义，但mTEC谱系的早期阶段仍然难以确定。在这里，我们利用体内靶向mTEC来解决它们的分化途径，并确定mTEC前体是否参与胸腺细胞的教育。我们发现mTECs起源于位于皮质-髓质交界处的一个血统承诺的、表达泊多普宁(PDPN)的祖细胞。PDPN+连接TECs(JTECs)代表一个独特的构建胸腺髓质的TEC群体，但仅部分支持负选择和胸腺细胞分化。此外，条件性基因打靶显示，在JTEC阶段取消替代的NF-kappa B信号通路完全阻止了mTEC的发育。综上所述，本研究确定jTECs是血统承诺的mTEC前体细胞，并表明依赖于NF-kappa B的jTECs向mTECs的进展是确保中枢耐受的关键。
The thymic epithelium forms specialized niches to enable thymocyte differentiation. While the common epithelial progenitor of medullary and cortical thymic epithelial cells (mTECs and cTECs) is well defined, early stages of mTEC lineage specification have remained elusive. Here, we utilized in vivo targeting of mTECs to resolve their differentiation pathways and to determine whether mTEC progenitors participate in thymocyte education. We found that mTECs descend from a lineage committed, podoplanin (PDPN)-expressing progenitor located at the cortico-medullary junction. PDPN+ junctional TECs (jTECs) represent a distinct TEC population that builds the thymic medulla, but only partially supports negative selection and thymocyte differentiation. Moreover, conditional gene targeting revealed that abrogation of alternative NF-kappa B pathway signaling in the jTEC stage completely blocked mTEC development. Taken together, this study identifies jTECs as lineage-committed mTEC progenitors and shows that NF-kappa B-dependent progression of jTECs to mTECs is critical to secure central tolerance.