Differential expression of Fas ligand in Th1 and Th2 cells is regulated by early growth response gene and NF-AT family members
Differential expression of Fas ligand in Th1 and Th2 cells is regulated by early growth response gene and NF-AT family members
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DOI：
10.4049/jimmunol.166.7.4534
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发表时间：
2001-04-01
影响因子：
4.4
通讯作者：
Weaver, CT
中科院分区：
文献类型：
--
作者：
Dzialo-Hatton, R;Milbrandt, J;Weaver, CT
激活的 T 细胞诱导表达 Fas 配体（CD95 配体）并导致携带 CD95 的细胞凋亡，是外周 T 细胞稳态和细胞毒性效应机制的关键组成部分。 Fas 配体表达的转录控制归因于许多因素，包括早期生长反应基因 2 (Egr2)、Egr3、Sp1 和 NF-AT，尽管 NF-AT 的直接贡献存在争议。本研究证实了 Egr 因子的作用，并表明 NF-AT 通过与 NF-AT 共有元件直接相互作用，对于鼠 Fas 配体的最佳表达至关重要。通过研究来自 DO11.10 TCR 转基因小鼠的 Th1 和 Th2 系中 Fas 配体的差异表达，进一步明确了这些因素的作用。对 Egr/NF-AT 复合位点的 EMSA 分析显示，在 Th2 细胞中 Sp1 被募集到该位点，但在 Th1 细胞中则不然。此外，凝胶位移分析表明，Th2 细胞中的 Egr1、2 和 3 以及 Th1 细胞中的 Egr1 和 2 在已知的 Egr 位点处结合，但不结合 Egr3。 Northern 分析证实了 Th1 细胞中缺乏 Egr3。 Th1 和 Th2 细胞对这些转录因子的差异使用表明不同 T 细胞谱系 Fas 配体差异表达的潜在机制。
Inducible expression of Fas ligand (CD95 ligand) by activated T cells and the resulting apoptosis of CD95-bearing cells is a critical component of peripheral T cell homeostasis and cytotoxic effector mechanisms. Transcriptional control of the expression of Fas ligand has been attributed to a number of factors, including early growth response gene 2 (Egr2), Egr3, Sp1, and NF-AT, although a direct contribution of NF-AT is controversial. The present study confirms a role for Egr factors and indicates that NF-AT is essential for optimal expression of murine Fas ligand through a direct interaction with an NF-AT consensus element. The role of these factors was further defined by studying the differential expression of Fas ligand in Th1 and Th2 lines derived from DO11.10 TCR transgenic mice. EMSA analyses of a composite Egr/NF-AT site showed recruitment of Sp1 to this site in Th2 cells, but not in Th1 cells. Furthermore, gel-shift analyses demonstrated the binding of Egr1, 2, and 3 in Th2 cells and Egr1 and 2, but not Egr3 in Th1 cells at a known Egr site. Northern analysis corroborated the lack of Egr3 in Th1 cells. Differential usage of these transcription factors by Th1 and Th2 cells suggests a potential mechanism underlying the differential expression of Fas ligand by distinct T cell lineages.