Positive and negative roles of the trans-acting T cell factor-1 for the acquisition of distinct ly-49 MHC class I receptors by NK cells
Positive and negative roles of the trans-acting T cell factor-1 for the acquisition of distinct ly-49 MHC class I receptors by NK cells
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DOI：
10.4049/jimmunol.166.10.6181
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发表时间：
2001-05-15
影响因子：
4.4
通讯作者：
Held, W
中科院分区：
文献类型：
--
作者：
Kunz, B;Held, W
Ly-49 基因家族的成员编码调节 NK 细胞功能的 I 类 MHC 特异性受体。由于 Ly-49 受体的组合分布，NK 细胞表现出相当大的克隆异质性。 Ly-49 受体 Ly-49A 的获得严格依赖于转录特征作用因子 T 细胞特异性因子 1 (TCF-1)。事实上，TCF-1 与 Ly-49a 启动子中的两个位点结合并调节其活性，表明 Ly-49a 基因是 TCF-1 的直接靶点。 TCF-1 缺陷导致其他 Ly-49 受体的使用发生改变。我们在这项研究中使用 TCF-1 β (2)-微球蛋白双缺陷小鼠证明，这些功能库的改变并不是由于 Ly-49/MHC I 类相互作用所致。我们的研究结果表明 TCF-1 依赖性细胞自主效应对多种 Ly-49 受体的获得有影响。除了减少受体使用（Ly-49A 和 D）外，我们还观察到在没有 TCF-1 的情况下没有效果（Ly-49C）并且受体使用显着增加（Ly-49G 和 I）。这些效应并非在所有情况下都与相应近端启动子中 TCF 结合位点的存在相关。因此，除了 TCF-1 与近端启动子结合之外，Ly-49 的获得也可能通过 TCF-1 与更远的顺式作用元件的结合和/或通过调节其他陷阱作用因子的表达来调节。与观察到的 TCF-1 对 Ly-49 受体获取的差异、正向或负向作用一致，报告基因测定揭示了某些近端 Ly-49 启动子中存在诱导和抑制 TCF 位点。这些发现揭示了 TCF-1 在 NK 细胞受体库形成中的重要作用。
Members of the Ly-49 gene family code for class I MHC-specific receptors that regulate NK cell function. Due to a combinatorial distribution of Ly-49 receptors, NK cells display considerable clonal heterogeneity. The acquisition of one Ly-49 receptor, Ly-49A is strictly dependent on the transcriptional traits-acting factor T cell-specific factor-1 (TCF-1). Indeed, TCF-1 binds to two sites in the Ly-49a promoter and regulates its activity, suggesting that the Ly-49a gene is a direct TCF-1 target. TCF-1 deficiency resulted in the altered usage of additional Ly-49 receptors. We show in this study, using TCF-1 beta (2)-microglobulin double-deficient mice, that these repertoire alterations are not due to Ly-49/MHC class I interactions. Our findings rather suggest a TCF-1-dependent, cell autonomous effect on the acquisition of multiple Ly-49 receptors. Besides reduced receptor usage (Ly-49A and D), we also observed no effect (Ly-49C) and significantly expanded (Ly-49G and I) receptor usage in the absence of TCF-1. These effects did not in all cases correlate with the presence of TCF binding sites in the respective proximal promoter. Therefore, besides TCF-1 binding to the proximal promoter, Ly-49 acquisition may also be regulated by TCF-1 binding to more distant cis-acting elements and/or by regulating the expression of additional traps-acting factors. Consistent with the observed differential, positive or negative role of TCF-1 for Ly-49 receptor acquisition, reporter gene assays revealed the presence of an inducing as well as a repressing TCF site in certain proximal Ly-49 promoters. These findings reveal an important role of TCF-1 for the formation of the NK cell receptor repertoire.