While the zinc finger transcription factors EGR1, EGR2, and EGR3 are recognized as critical for T-cell function, the role of EGR4 remains unstudied. Here, we show that EGR4 is rapidly upregulated upon TCR engagement, serving as a critical "brake" on T-cell activation. Hence, TCR engagement of EGR4-/- T cells leads to enhanced Ca2+ responses, driving sustained NFAT activation and hyperproliferation. This causes profound increases in IFNγ production under resting and diverse polarizing conditions that could be reversed by pharmacological attenuation of Ca2+ entry. Finally, an in vivo melanoma lung colonization assay reveals enhanced anti-tumor immunity in EGR4-/- mice, attributable to Th1 bias, Treg loss, and increased CTL generation in the tumor microenvironment. Overall, these observations reveal for the first time that EGR4 is a key regulator of T-cell differentiation and function.

中文翻译：

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EGR4 对 Ca2+ 信号的抑制在体内控制 Th1 分化和抗癌免疫。

虽然锌指转录因子 EGR1、EGR2 和 EGR3 被认为对 T 细胞功能至关重要，但 EGR4 的作用仍未得到研究。在这里，我们表明 EGR4 在 TCR 参与后迅速上调，作为 T 细胞激活的关键“制动器”。因此，EGR4-/- T 细胞的 TCR 参与导致增强的 Ca2+ 反应，驱动持续的 NFAT 激活和过度增殖。这导致在静息和不同的极化条件下 IFNγ 产生的显着增加，这可以通过药理学减弱 Ca2+ 进入来逆转。最后，体内黑色素瘤肺定植试验揭示了 EGR4-/- 小鼠的抗肿瘤免疫增强，这归因于肿瘤微环境中的 Th1 偏倚、Treg 丢失和 CTL 生成增加。全面的，