Suppression of Ca2+ signals by EGR4 controls Th1 differentiation and anti‐cancer immunity in vivo.

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. Synopsis: EGR proteins regulate T cell development and differentiation, but no role for EGR4 has previously been shown. T cell activation upregulates EGR4, whereas EGR4−/− T cells exhibit increased Ca2+ responses, promoting Th1 bias and anti‐cancer immunity. EGR4 is expressed in activated T cells.EGFR4 suppresses Ca2+ responses by regulating KCa3.1 and Kv1.3 expression.In the absence of EGR4, Ca2+‐dependent NFAT activation drives Th1 differentiation.EGR4−/− T cells exhibit enhanced anti‐cancer immunity. [ABSTRACT FROM AUTHOR]