Translational repression of pre-formed cytokine-encoding mRNA prevents chronic activation of memory T cells

Authors

Fiamma Salerno, Universiteit van Amsterdam
Sander Engels, Universiteit van Amsterdam
Maartje van den Biggelaar, Sanquin Research
Floris P.J. van Alphen, Sanquin Research
Aurelie Guislain, Universiteit van Amsterdam
Wanqi Zhao, Universiteit van Amsterdam
Deborah L. Hodge, National Cancer Institute at Frederick
Sarah E. Bell, The Babraham Institute
Jan Paul Medema, Universiteit van Amsterdam
Marieke von Lindern, Universiteit van Amsterdam
Martin Turner, The Babraham Institute
Howard A. Young, National Cancer Institute at FrederickFollow
Monika C. Wolkers, Universiteit van AmsterdamFollow

Date of this Version

8-1-2018

Citation

Nat ure Immunology VOL 19 AUGUST 2018, 828–837

https://doi.org/10.1038/s41590-018-0155-6

Comments

U.S. government work

Abstract

Memory T cells are critical for the immune response to recurring infections. Their instantaneous reactivity to pathogens is empowered by the persistent expression of cytokine-encoding mRNAs. How the translation of proteins from pre-formed cytokine-encoding mRNAs is prevented in the absence of infection has remained unclear. Here we found that protein production in memory T cells was blocked via a 3′ untranslated region (3′ UTR)-mediated process. Germline deletion of AU-rich elements (AREs) in the Ifng-3′ UTR led to chronic cytokine production in memory T cells. This aberrant protein production did not result from increased expression and/or half-life of the mRNA. Instead, AREs blocked the recruitment of cytokine-encoding mRNA to ribosomes; this block depended on the ARE-binding protein ZFP36L2. Thus, AREs mediate repression of translation in mouse and human memory T cells by preventing undesirable protein production from pre-formed cytokine-encoding mRNAs in the absence of infection.