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.