Suppression of Ca 2+ signals by EGR 4 controls Th1 differentiation and anti‐cancer immunity in vivo

While the zinc finger transcription factors EGR 1, EGR 2, and EGR 3 are recognized as critical for T‐cell function, the role of EGR 4 remains unstudied. Here, we show that EGR 4 is rapidly upregulated upon TCR engagement, serving as a critical “brake” on T‐cell activation. Hence, TCR engagement of EGR 4 −/− T cells leads to enhanced Ca 2+ responses, driving sustained NFAT activation and hyperproliferation. This causes profound increases in IFN γ production under resting and diverse polarizing conditions that could be reversed by pharmacological attenuation of Ca 2+ entry. Finally, an in vivo melanoma lung colonization assay reveals enhanced anti‐tumor immunity in EGR 4 −/− mice, attributable to Th1 bias, Treg loss, and increased CTL generation in the tumor microenvironment. Overall, these observations reveal for the first time that EGR 4 is a key regulator of T‐cell differentiation and function.