NF-AT-mediated expression of TGF-β1 in tolerant T cells
NF-AT-mediated expression of TGF-β1 in tolerant T cells
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DOI：
10.4049/jimmunol.178.5.3067
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发表时间：
2007-03-01
影响因子：
4.4
通讯作者：
Hozumi, Nobumichi
中科院分区：
文献类型：
--
作者：
Nakano, Naoko;Hosokawa, Hiroyuki;Hozumi, Nobumichi
在胸腺中 T 细胞发育过程中，一定数量的自身反应性胸腺细胞分化为调节性 T 细胞，抑制其他有害的自身反应性 T 细胞。在表达特异性识别蛾细胞色素c的TCR和蛾细胞色素c配体的转基因小鼠中，大部分CD4(+)T细胞在Ag刺激下表达CD25并分泌TGF-β1。由于这些 T 细胞的 TGF-β1 表达可被环孢菌素 A（一种 NF-AT 抑制剂）降低，因此通过表征 TGF-β1 启动子中的 NF-AT 反应元件来解决 T 细胞中 NF-AT 介导的 TGF-β1 表达问题。在 T 细胞 68-41 杂交瘤细胞的转染实验中对小鼠 TGF-β 1 启动子（-1799 至 +793）的分析检测到近端启动子区域中位置 +268 和 +288 处的 NF-AT 结合位点。通过染色质免疫沉淀分析，仅在耐受性 CD4+ T 细胞中检测到 NF-AT 与该区域的结合，而在完全激活的 CD4+ T 细胞中未检测到 NF-AT 与该区域的结合。这些 NF-AT 位点的激活足以诱导 TGF-β1 启动子活性；然而，由于 Ag 的完全刺激，额外的信号传导阻断了 NF-AT 介导的 TGF-β 1 表达。 TGF-β1启动子的这种抑制是由-1079至-406区域介导的，其中-821位GATA结合基序的缺失消除了NF-AT介导的TGF-β1启动子的激活。因此，T 细胞中的 TGF-β1 表达受到多种调节因子的控制，这些调节因子在响应部分或全部 TCR 激活时具有不同的功能。
During T cell development in the thymus, a certain population of self-reactive thymocytes differentiates into regulatory T cells that suppress otherwise harmful self-reactive T cells. In transgenic mice expressing both TCR that specifically recognizes moth cytochrome c and the moth cytochrome c ligand, a large proportion of CD4(+) T cells expresses CD25 and secretes TGF-beta 1 upon Ag stimulation. Because TGF-beta 1 expression by these T cells can be decreased by cyclosporin A, a NF-AT inhibitor, NF-AT-mediated TGF-beta 1 expression in T cells was addressed by characterizing a NF-AT response element in the TGF-beta 1 promoter. Analysis of the mouse TGF-beta 1 promoter (-1799 to +793) in transfection experiments in T cell 68-41 hybridoma cells detected NF-AT binding sites at positions +268 and +288 in the proximal promoter region. Binding of NF-AT to this region was detected only in tolerant CD4+ T cells, but not in fully activated CD4+ T cells by chromatin immunoprecipitation assays. Activation of these NF-AT sites was sufficient to induce TGF-beta 1 promoter activity; however, additional signaling due to full Ag stimulation blocked NF-AT-mediated TGF-beta 1 expression. This suppression of the TGF-beta 1 promoter is mediated by the -1079 to -406 region, in which deletion of a GATA-binding motif at position -821 abrogates NF-AT-mediated activation of the TGF-beta 1 promoter. Therefore, TGF-beta 1 expression in T cells is controlled by multiple regulatory factors that have distinct functions in response to partial or full TCR activation.