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

Nat Immunol. 2018 Aug;19(8):828-837. doi: 10.1038/s41590-018-0155-6. Epub 2018 Jul 9.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics*
  • AU Rich Elements / genetics*
  • Animals
  • Cells, Cultured
  • Epigenetic Repression
  • Immunologic Memory
  • Interferon-gamma / genetics*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Peptide Chain Elongation, Translational
  • RNA, Messenger / genetics*
  • Ribosomes / metabolism
  • T-Lymphocytes / immunology*
  • Tristetraprolin / genetics
  • Tristetraprolin / metabolism

Substances

  • 3' Untranslated Regions
  • RNA, Messenger
  • Tristetraprolin
  • Zfp36 protein, mouse
  • Interferon-gamma