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Suppression of Ca 2+ signals by EGR 4 controls Th1 differentiation and anti‐cancer immunity in vivo
Author(s) -
MookerjeeBasu Jayati,
Hooper Robert,
Gross Scott,
Schultz Bryant,
Go Christina K,
Samakai Elsie,
Ladner Jonathan,
Nicolas Emmanuelle,
Tian Yuanyuan,
Zhou Bo,
Zaidi M Raza,
Tourtellotte Warren,
He Shan,
Zhang Yi,
Kappes Dietmar J,
Soboloff Jonathan
Publication year - 2020
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201948904
Subject(s) - in vivo , immunity , chemistry , microbiology and biotechnology , cancer , biology , immune system , cancer research , immunology , genetics
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.