Suppression of Ca 2+ signals by EGR4 controls Th1 differentiation and anti-cancer immunity in vivo

EMBO Rep. 2020 May 6;21(5):e48904. doi: 10.15252/embr.201948904. Epub 2020 Mar 25.

Abstract

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.

Keywords: EGR4; K channels; STIM1; Th1 differentiation; cancer immunity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Signaling*
  • Cell Differentiation
  • Early Growth Response Transcription Factors*
  • Lymphocyte Activation
  • Mice
  • Neoplasms*
  • Tumor Microenvironment
  • Zinc Fingers

Substances

  • Early Growth Response Transcription Factors
  • Egr4 protein, mouse