Retinoic Acid-Induced CCR9 Expression Requires Transient TCR Stimulation and Cooperativity between NFATc2 and the Retinoic Acid Receptor/Retinoid X Receptor Complex
Retinoic Acid-Induced CCR9 Expression Requires Transient TCR Stimulation and Cooperativity between NFATc2 and the Retinoic Acid Receptor/Retinoid X Receptor Complex
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DOI：
10.4049/jimmunol.1000913
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发表时间：
2011-01-15
影响因子：
4.4
通讯作者：
Iwata, Makoto
中科院分区：
文献类型：
--
作者：
Ohoka, Yoshiharu;Yokota, Aya;Iwata, Makoto
视黄酸（RA）通过诱导趋化因子受体CCR 9和整联蛋白α 4 β 7的表达在活化后在T细胞上印刻肠道归巢特异性。CCR 9的表达似乎比α 4 β 7的表达更依赖于RA，但其分子机制尚不清楚。在这篇文章中，我们发现NFAT亚型NFATc 1和NFATc 2直接与RA受体（RAR）和维甲酸X受体（RXR）相互作用，但在RA诱导的小鼠幼稚CD 4（+）T细胞上CCR 9表达中发挥不同的作用。TCR刺激6-24小时是获得对RA的反应性所必需的，并诱导NFATc 1和NFATc 2的激活。然而，RA未能诱导CCR 9的表达，只要TCR刺激继续。在终止TCR刺激或向培养物中加入环孢菌素A后，Ccr 9基因转录被诱导，伴随着NFATc 1的失活和NFATc 2的持续活化。报告基因和DNA亲和沉淀分析表明，NFATc 2与两个NFAT结合位点的结合以及RAR/RXR复合物与小鼠Ccr 9基因5 '侧翼区的RA应答元件半位点的结合对于RA诱导的启动子活性是至关重要的。NFATc 2直接结合RAR α和RXR α，并增强RAR α与RA反应元件半位点的结合。NFATc 1也与NFAT结合位点结合，并直接与RAR α和RXR α结合，但它抑制NFATc 2依赖性启动子活性。这些结果表明，NFATc 2和RAR/RXR复合物之间的协同性对于T细胞上的CCR 9表达是必不可少的，并且NFATc 1干扰NFATc 2的作用。免疫学杂志，2011，186：733-744。
Retinoic acid (RA) imprints gut-homing specificity on T cells upon activation by inducing the expression of chemokine receptor CCR9 and integrin alpha 4 beta 7. CCR9 expression seemed to be more highly dependent on RA than was the alpha 4 beta 7 expression, but its molecular mechanism remained unclear. In this article, we show that NFAT isoforms NFATc1 and NFATc2 directly interact with RA receptor (RAR) and retinoid X receptor (RXR) but play differential roles in RA-induced CCR9 expression on murine naive CD4(+) T cells. TCR stimulation for 6-24 h was required for the acquisition of responsiveness to RA and induced activation of NFATc1 and NFATc2. However, RA failed to induce CCR9 expression as long as TCR stimulation continued. After terminating TCR stimulation or adding cyclosporin A to the culture, Ccr9 gene transcription was induced, accompanied by inactivation of NFATc1 and sustained activation of NFATc2. Reporter and DNA-affinity precipitation assays demonstrated that the binding of NFATc2 to two NFAT-binding sites and that of the RAR/RXR complex to an RA response element half-site in the 5'-flanking region of the mouse Ccr9 gene were critical for RA-induced promoter activity. NFATc2 directly bound to RAR alpha and RXR alpha, and it enhanced the binding of RARa to the RA response element half-site. NFATc1 also bound to the NFAT-binding sites and directly to RAR alpha and RXR alpha, but it inhibited the NFATc2-dependent promoter activity. These results suggest that the cooperativity between NFATc2 and the RAR/RXR complex is essential for CCR9 expression on T cells and that NFATc1 interferes with the action of NFATc2. The Journal of Immunology, 2011, 186: 733-744.