The 2'-O-methylation status of a single guanosine controls transfer RNA-mediated Toll-like receptor 7 activation or inhibition

J Exp Med. 2012 Feb 13;209(2):235-41. doi: 10.1084/jem.20111075. Epub 2012 Feb 6.


Foreign RNA serves as pathogen-associated molecular pattern (PAMP) and is a potent immune stimulator for innate immune receptors. However, the role of single bacterial RNA species in immune activation has not been characterized in detail. We analyzed the immunostimulatory potential of transfer RNA (tRNA) from different bacteria. Interestingly, bacterial tRNA induced type I interferon (IFN) and inflammatory cytokines in mouse dendritic cells (DCs) and human peripheral blood mononuclear cells (PBMCs). Cytokine production was TLR7 dependent because TLR7-deficient mouse DCs did not respond and TLR7 inhibitory oligonucleotides inhibited tRNA-mediated activation. However, not all bacterial tRNA induced IFN-α because tRNA from Escherichia coli Nissle 1917 and Thermus thermophilus were non-immunostimulatory. Of note, tRNA from an E. coli knockout strain for tRNA (Gm18)-2'-O-methyltransferase (trmH) regained immunostimulatory potential. Additionally, in vitro methylation of this immunostimulatory Gm18-negative tRNA with recombinant trmH from T. thermophilus abolished its IFN-α inducing potential. More importantly, Gm18-modified tRNA acted as TLR7 antagonist and blocked IFN-α induction of influenza A virus-infected PBMCs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteria / genetics*
  • Bacteria / immunology
  • Chromatography, High Pressure Liquid
  • Dendritic Cells / immunology
  • Guanosine / metabolism*
  • Humans
  • Immunity, Innate / immunology*
  • Immunization
  • Interferon-alpha / metabolism
  • Leukocytes, Mononuclear / immunology
  • Membrane Glycoproteins / antagonists & inhibitors
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / immunology*
  • Mice
  • Mice, Knockout
  • Oligonucleotides
  • RNA, Transfer / immunology*
  • RNA, Transfer / pharmacology
  • Toll-Like Receptor 7 / antagonists & inhibitors
  • Toll-Like Receptor 7 / genetics
  • Toll-Like Receptor 7 / immunology*
  • tRNA Methyltransferases / genetics
  • tRNA Methyltransferases / metabolism*


  • Interferon-alpha
  • Membrane Glycoproteins
  • Oligonucleotides
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • Guanosine
  • RNA, Transfer
  • tRNA Methyltransferases