Early growth response 1 and NF-ATc1 act in concert to promote thymocyte development beyond the β-Selection checkpoint
Early growth response 1 and NF-ATc1 act in concert to promote thymocyte development beyond the β-Selection checkpoint
复制标题
DOI：
10.4049/jimmunol.179.7.4694
复制
发表时间：
2007-10-01
影响因子：
4.4
通讯作者：
Wiest, David L.
中科院分区：
文献类型：
--
作者：
Koltsova, Ekaterina K.;Ciofani, Maria;Wiest, David L.
未成熟 T 细胞前体的发育超出 β 选择检查点是由前 TCR 复合物转导的信号调节的。 TCR 前诱导的分化程序是由转录因子网络精心策划的，这些转录因子用于整合该信号传导信息。这些转录因子包括早期生长反应 (Egr) 和 NF-AT 家族的转录因子。在这项研究中，我们证明Egr1和NF-ATc1共同作用，促进T细胞前体细胞从β选择检查点发育到CD8未成熟单阳性和CD4(+)CD8(+)双阳性阶段。此外，我们发现 Egr1 和 NF-AT 协同诱导 DNA 结合抑制剂 3 (ID3) 的表达，这是一种已知在胸腺细胞正选择中发挥重要作用的调节因子，但之前并未证明是 β-选择所必需的。重要的是，我们在这项研究中表明，Id3 缺陷会消除异位表达的 Egr1 促进穿过 β 选择检查点的能力。在这种情况下，Id3 可能对于穿越 β 选择检查点至关重要，因为其他 DNA 结合家族成员抑制剂无法补偿，因为转基因 Egr1 不会诱导 DNA 结合抑制剂 1 (Id1) 或 2 (Id2) 的表达。总而言之，这些数据表明 Id3 是一个协同诱导的靶标，对于 Egr 介导的 β 选择检查点之外的发育促进非常重要。此外，这些数据表明 ERK 和钙信号通路可能分别通过 Egr1 和 NF-ATc1 的协同作用在 β 选择过程中汇聚。
Development of immature T cell precursors beyond the beta-selection checkpoint is regulated by signals transduced by the pre-TCR complex. The pre-TCR-induced differentiation program is orchestrated by a network of transcription factors that serve to integrate this signaling information. Among these transcription factors are those of the early growth response (Egr) and NF-AT families. In this study, we demonstrate that Egr1 and NF-ATc1 act together to promote development of T cell precursors beyond the beta-selection checkpoint to the CD8 immature single-positive and CD4(+)CD8(+) double-positive stages. Moreover, we find that Egr1 and NF-AT cooperatively induce the expression of inhibitor of DNA binding 3 (ID3), a regulatory factor known to play an important role in positive selection of thymocytes, but not previously demonstrated to be required for beta-selection. Importantly, we show in this study that Id3 deficiency abrogates the ability of ectopically expressed Egr1 to promote traversal of the beta-selection checkpoint. Id3 is presumably essential for traversal of the beta-selection checkpoint in this context because of the inability of other inhibitor of DNA binding family members to compensate, since transgenic Egr1 does not induce expression of inhibitor of DNA binding 1 (Id1) or 2 (Id2). Taken together, these data demonstrate that Id3 is a cooperatively induced target that is important for Egr-mediated promotion of development beyond the beta-selection checkpoint. Moreover, these data indicate that the ERK and calcium signaling pathways may converge during beta-selection through the concerted action of Egr1 and NF-ATc1, respectively.