Sustained expression of pre-TCR induced beta-catenin in post-beta-selection thymocytes blocks T cell development.
Sustained expression of pre-TCR induced beta-catenin in post-beta-selection thymocytes blocks T cell development.
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DOI：
10.4049/jimmunol.182.2.759
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发表时间：
2009-01-15
期刊：
影响因子：
--
通讯作者：
Sen JM
中科院分区：
文献类型：
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作者：
Xu M;Sharma A;Hossain MZ;Wiest DL;Sen JM
Pre-TCR和IL-7R信号调节胸腺细胞的β选择，然后必须下调以进一步发育。然而，控制下调的分子事件仍然未知。我们和其他人之前已经证明β-catenin与TCF合作调节β选择。在本文中，我们证明了β-catenin的表达受到胸腺内信号的严格调控，在tcr前胸腺细胞中表达水平最高，在β选择后胸腺细胞中表达水平下调。tcr前诱导的β-catenin调节tcr前信号传导的初始阶段，包括早期生长反应（Egr）基因的表达，但必须下调以表达RORγt，这是成熟到CD4+CD8+双阳性（DP）阶段所必需的。持续表达β-catenin导致产生IL-7R-、Egr-和tgf - β表达的pre-DP胸腺细胞，这些细胞在发育中被阻断。这些数据与β选择后，tcr诱导前β-catenin表达必须返回背景水平才能有效过渡到DP阶段的模型一致。
Pre-TCR and IL-7R signals regulate β-selection of thymocytes and then must be down-regulated for further development. However, the molecular events that control down-regulation remain unknown. We and others have previously shown that β-catenin in cooperation with TCF regulates β-selection. In this paper, we demonstrate that β-catenin expression is stringently regulated by intrathymic signals, it is expressed at the highest levels in the pre-TCR signaled thymocytes, and is down-regulated in post-β-selection thymocytes. Pre-TCR-induced β-catenin regulates initial stages of pre-TCR signaling including expression of early growth response (Egr) genes but must be down-regulated to express RORγt, which is essential for maturation to the CD4+CD8+ double positive (DP) stage. Sustained expression of β-catenin results in the generation of IL-7R-, Egr-, and TGFβ-expressing pre-DP thymocytes that are blocked in development. These data are consistent with a model in which post-β-selection, pre-TCR-induced β-catenin expression must return to background levels for efficient transition to the DP stage.