Delta-like 4 is indispensable in thymic environment specific for T cell development.
Delta-like 4 is indispensable in thymic environment specific for T cell development.
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DOI：
10.1084/jem.20080134
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发表时间：
2008-10-27
影响因子：
15.3
通讯作者：
Habu, Sonoko
中科院分区：
文献类型：
--
作者：
Hozumi, Katsuto;Mailhos, Carolina;Negishi, Naoko;Hirano, Ken-ichi;Yahata, Takashi;Ando, Kiyoshi;Zuklys, Saulius;Hollaender, Georg A.;Shima, David T.;Habu, Sonoko
胸腺微环境是体内T细胞发育所必需的。然而，体外研究表明，当造血祖细胞通过δ样（Dll）1或Dll 4获得Notch信号传导时，它们在缺乏胸腺微环境的情况下分化成T细胞谱系。然而，目前尚不清楚胸腺是否通过提供Notch信号特异性地支持T细胞发育。为了解决这个问题，我们产生了小鼠loxP侧翼等位基因Dll4和诱导基因缺失特异性胸腺上皮细胞（TEC）。在突变小鼠的胸腺中，上皮细胞上Dll 4的表达被废除，并且携带Notch 1的细胞内片段（ICN 1）的造血细胞的比例显著降低。与此相对应，在胸腺中未检测到CD4 CD8双阳性或单阳性T细胞。进一步的分析表明，双阴性细胞部分缺乏T细胞祖细胞。ICN1在造血祖细胞中的强制表达恢复了胸腺T细胞分化，即使当TEC缺乏Dll4时。这些结果表明，胸腺特异性的环境，决定T细胞的命运，不可避免地需要Dll4的表达，以诱导Notch信号在胸腺移民细胞。
The thymic microenvironment is required for T cell development in vivo. However, in vitro studies have shown that when hematopoietic progenitors acquire Notch signaling via Delta-like (Dll)1 or Dll4, they differentiate into the T cell lineage in the absence of a thymic microenvironment. It is not clear, however, whether the thymus supports T cell development specifically by providing Notch signaling. To address this issue, we generated mice with a loxP-flanked allele of Dll4 and induced gene deletion specifically in thymic epithelial cells (TECs). In the thymus of mutant mice, the expression of Dll4 was abrogated on the epithelium, and the proportion of hematopoietic cells bearing the intracellular fragment of Notch1 (ICN1) was markedly decreased. Corresponding to this, CD4 CD8 double-positive or single-positive T cells were not detected in the thymus. Further analysis showed that the double-negative cell fraction was lacking T cell progenitors. The enforced expression of ICN1 in hematopoietic progenitors restored thymic T cell differentiation, even when the TECs were deficient in Dll4. These results indicate that the thymus-specific environment for determining T cell fate indispensably requires Dll4 expression to induce Notch signaling in the thymic immigrant cells.
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DOI：
10.1084/jem.20061442
发表时间：
2007-02-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Besseyrias V;Fiorini E;Strobl LJ;Zimber-Strobl U;Dumortier A;Koch U;Arcangeli ML;Ezine S;Macdonald HR;Radtke F
通讯作者：
Radtke F
影响因子：
20.3
作者：
Mancini, SJC;Mantei, N;Radtke, F
通讯作者：
Radtke, F
影响因子：
64.8
作者：
MOMBAERTS, P;CLARKE, AR;TONEGAWA, S
通讯作者：
TONEGAWA, S
影响因子：
4.4
作者：
Han, H;Tanigaki, K;Honjo, T
通讯作者：
Honjo, T
维持T细胞规范和分化需要经常性的Notch受体 - 配体相互作用。
影响因子：
15.3
作者：
Schmitt, TM;Ciofani, M;Petrie, HT;Zúñiga-Pflücker, JC
通讯作者：
Zúñiga-Pflücker, JC