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Mookerjee-Basu J , Hooper R , Gross S , Schultz B , Go CK , Samakai E , Ladner J , Nicolas E , Tian Y , Zhou B , Zaidi MR , Tourtellotte W , He S , Zhang Y , Kappes DJ , Soboloff J
Suppression of Ca(2+) signals by EGR4 controls Th1 differentiation and anti-cancer immunity in vivo
EMBO Rep. 2020 Mar 25;21(5) :e48904
PMID: 32212315    PMCID: PMC7202224    URL: https://www.ncbi.nlm.nih.gov/pubmed/32212315
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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 Ca(2+) responses, driving sustained NFAT activation and hyperproliferation. This causes profound increases in IFNgamma 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 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.
Notes
1469-3178 Mookerjee-Basu, 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 ORCID: https://orcid.org/0000-0002-9112-509X Soboloff, Jonathan ORCID: https://orcid.org/0000-0001-5192-1297 R01GM107179/HHS|NIH|National Institute of General Medical Sciences (NIGMS) R01 CA193711/CA/NCI NIH HHS/United States K26OD010945/HHS|NIH|National Institute of Neurological Disorders and Stroke (NINDS) R01NS040748/HHS|NIH|National Institute of Neurological Disorders and Stroke (NINDS) W J Avery Foundation R01AI068907/HHS|NIH|National Institute of Allergy and Infectious Diseases (NIAID) 1R56AI43256/HHS|NIH|National Institute of Allergy and Infectious Diseases (NIAID) R01GM117907/HHS|NIH|National Institute of General Medical Sciences (NIGMS) P30CA006927/HHS|NIH|National Cancer Institute (NCI) K02NS046468/HHS|NIH|National Institute of Neurological Disorders and Stroke (NINDS) Journal Article England EMBO Rep. 2020 Mar 25:e48904. doi: 10.15252/embr.201948904.