Department of Molecular Pathology, Institute of Pathology, University of Wurzburg, D-97080 Wurzburg, Germany.
Proc Natl Acad Sci U S A. 2011 Feb 8;108(6):2480-5. doi: 10.1073/pnas.1009463108. Epub 2011 Jan 24.
Inducible cAMP early repressor (ICER) is a transcriptional repressor, which, because of alternate promoter use, is generated from the 3' region of the cAMP response modulator (Crem) gene. Its expression and nuclear occurrence are elevated by high cAMP levels in naturally occurring regulatory T cells (nTregs). Using two mouse models, we demonstrate that nTregs control the cellular localization of ICER/CREM, and thereby inhibit IL-2 synthesis in conventional CD4(+) T cells. Ablation of nTregs in depletion of regulatory T-cell (DEREG) mice resulted in cytosolic localization of ICER/CREM and increased IL-2 synthesis upon stimulation. Direct contacts between nTregs and conventional CD4(+) T cells led to nuclear accumulation of ICER/CREM and suppression of IL-2 synthesis on administration of CD28 superagonistic (CD28SA) Ab. In a similar way, nTregs communicated with B cells and induced the cAMP-driven nuclear localization of ICER/CREM. High levels of ICER suppressed the induction of nuclear factor of activated T cell c1 (Nfatc1) gene in T cells whose inducible Nfatc1 P1 promoter bears two highly conserved cAMP-responsive elements to which ICER/CREM can bind. These findings suggest that nTregs suppress T-cell responses by the cAMP-dependent nuclear accumulation of ICER/CREM and inhibition of NFATc1 and IL-2 induction.
可诱导的 cAMP 早期阻遏物（ICER）是一种转录阻遏物，由于其交替使用启动子，因此是从 cAMP 反应调节剂（Crem）基因的 3' 区域产生的。在天然存在的调节性 T 细胞（nTregs）中，高 cAMP 水平会导致其表达和核内出现增加。使用两种小鼠模型，我们证明 nTregs 控制 ICER/CREM 的细胞定位，并由此抑制常规 CD4(+) T 细胞中的 IL-2 合成。在消耗调节性 T 细胞（DEREG）小鼠中消除 nTregs 导致 ICER/CREM 的细胞质定位，并在刺激时增加 IL-2 合成。nTregs 与常规 CD4(+) T 细胞之间的直接接触导致 ICER/CREM 在细胞核中的积累，并在给予 CD28 超激动剂（CD28SA）Ab 时抑制 IL-2 合成。以类似的方式，nTregs 与 B 细胞通讯，并诱导 ICER/CREM 的 cAMP 驱动的核定位。高水平的 ICER 抑制了 T 细胞中诱导型 Nfatc1 P1 启动子上的核因子活化 T 细胞 c1（Nfatc1）基因的诱导，该启动子具有两个高度保守的 cAMP 反应元件，ICER/CREM 可以与之结合。这些发现表明，nTregs 通过 ICER/CREM 的 cAMP 依赖性核积累以及抑制 NFATc1 和 IL-2 诱导来抑制 T 细胞反应。
