IL-4-induced gene 1 maintains high Tob1 expression that contributes to TCR unresponsiveness in human T helper 17 cells
IL-4-induced gene 1 maintains high Tob1 expression that contributes to TCR unresponsiveness in human T helper 17 cells
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DOI：
10.1002/eji.201344047
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发表时间：
2014-03-01
影响因子：
5.4
通讯作者：
Annunziato, Francesco
中科院分区：
文献类型：
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作者：
Santarlasci, Veronica;Maggi, Laura;Annunziato, Francesco
与其他T细胞亚群相比，人类Th17细胞的增殖能力有限。我们已经证明，由于IL-4诱导的基因1(IL4I1)上调，人类Th17细胞显示出IL-2的产生受损。在这里，我们发现在人类Th17细胞中，IL4I1也保持着高水平的Tob1，这是ToB/BTG(B细胞易位基因)抗增殖蛋白家族的成员，它阻止了TCR刺激介导的细胞周期进展。事实上，在静息和TCR激活的条件下，Th17细胞都比Th1细胞表现出更高的Tob1水平。因此，细胞周期的正调控因子(细胞周期蛋白A、B、C、E和CDK2)以及促进Tob1降解的Skp2在Th17细胞中的表达低于Th1细胞。TAB1在人Th17细胞中的表达与RAR(维甲酸受体)相关的孤儿受体C(RORC)和IL4I1水平有关。然而，RORC不直接参与Tob1的表达调控，而IL4I1在Th17细胞中的沉默导致Tob1表达的显著降低。这些数据表明，人Th17细胞中IL4I1的上调不仅通过阻断参与IL-2启动子激活的分子途径，而且通过维持高水平的Tob1来限制其TCR介导的扩张，这损害了进入细胞周期的能力。
Human Th17 cells have a limited proliferative capacity compared to other T-cell subsets. We have shown that human Th17 cells display impaired IL-2 production due to IL-4-induced gene 1 (IL4I1) upregulation. Here, we show that in human Th17 cells, IL4I1 also maintains high levels of Tob1, a member of the Tob/BTG (B-cell traslocation gene) antiproliferative protein family, which prevents cell-cycle progression mediated by TCR stimulation. Indeed, Th17 cells exhibited higher levels of Tob1 than Th1 cells in both resting and TCR-activated conditions. Accordingly, the expression of positive regulators of the cell cycle (cyclin A, B, C, and E and Cdk2), as well as of Skp2, which promotes Tob1 degradation, was lower in Th17 cells than in Th1 cells. Tob1 expression in human Th17 cells correlated with both RAR (retinoic acid receptor)-related orphan receptor C (RORC) and IL4I1 levels. However, RORC was not directly involved in the regulation of Tob1 expression, whereas IL4I1 silencing in Th17 cells induced a substantial decrease of Tob1 expression. These data suggest that IL4I1 upregulation in human Th17 cells limits their TCR-mediated expansion not only by blocking the molecular pathway involved in the activation of the IL-2 promoter, but also by maintaining high levels of Tob1, which impairs entry into the cell cycle.