Frontline: ICER/CREM-mediated transcriptional attenuation of IL-2 and its role in suppression by regulatory T cells
Frontline: ICER/CREM-mediated transcriptional attenuation of IL-2 and its role in suppression by regulatory T cells
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DOI：
10.1002/eji.200636510
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发表时间：
2007-04-01
影响因子：
5.4
通讯作者：
Sakaguchi, Shimon
中科院分区：
文献类型：
--
作者：
Bodor, Josef;Fehervari, Zoltan;Sakaguchi, Shimon
在此，我们报告了诱导型cAMP早期阻遏物/cAMP反应元件调节物（ICER/CREM）在CD25（+）CD4（+）调节性T细胞（T-R）检测中主要在活化的Foxp3（-）效应T细胞中早期被诱导，并且这种诱导与表达IL-2的T细胞数量的急剧减少相关。重要的是，在应答者CD25（-）CD4（+）T细胞中靶向ICER/CREM的RNAi拮抗T-R介导的抑制。此外，初始CD25（-）CD4（+）T细胞中Foxp3的强制表达诱导具有调节表型的T细胞中ICER/CREM的组成型表达。Foxp3促进ICER/CREM在Foxp3转导子以及CD25（-）应答T细胞中的表达，这表明在抑制测定中TR功能的诱导可能利用接触依赖性相互作用。事实上，CTLA-4阻断或使用137缺陷型CD25（-）应答T细胞防止ICER/CREM积累并导致IL-2表达的拯救。因此，我们认为CTLA-4与活化的Foxp3（-）效应T细胞上表达的137个配体结合导致ICER/CREM介导的IL-2转录减弱。总的来说，这些数据表明TR细胞中的Foxp3表达通过诱导激活的CD 25（+）Foxp3（-）T细胞效应器中的组成性ICER/CREM表达，以接触依赖性方式施加抑制，从而阻止它们产生IL-2。
Here, we report that inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) is induced early in CD25(+)CD4(+) regulatory T cell (T-R) assays mainly in activated Foxp3(-) effector T cells and this induction correlates with sharp decrease in number of IL-2-expressing T cells. Importantly, RNAi targeting of ICER/CREM in responder CD25(-)CD4(+) T cells antagonizes T-R-mediated suppression. Moreover, forced expression of Foxp3 in naive CD25(-)CD4(+) T cells induces constitutive expression of ICER/CREM in T cells with a regulatory phenotype. Foxp3 facilitates expression of ICER/CREM both in Foxp3 transductants as well as CD25(-) responder T cells suggesting that induction of TR function in suppression assays may utilize contact-dependent interaction. Indeed, CTLA-4 blockade or use of 137-deficient CD25(-) responder T cells prevents ICER/CREM accumulation and leads to the rescue of IL-2 expression. Therefore, we propose that CTLA-4 binding to 137 ligands expressed on activated ligandbearing Foxp3(-) effector T cells results in ICER/CREM-mediated transcriptional attenuation of IL-2. Collectively, these data suggest that Foxp3 expression in TR cells imposes suppression in contact-dependent fashion by induction of constitutive ICER/CREM expression in activated CD25(+) Foxp3(-) T cell effectors thus preventing them from producing IL-2.