The DNA sugar backbone 2' deoxyribose determines toll-like receptor 9 activation

Immunity. 2008 Mar;28(3):315-23. doi: 10.1016/j.immuni.2008.01.013.


CpG motifs within phosphorothioate (PS)-modified DNA drive Toll-like receptor 9 (TLR9) activation, but the rules governing recognition of natural phosphodiester (PD) DNA are less understood. Here, we showed that the sugar backbone determined DNA recognition by TLR9. Homopolymeric, base-free PD 2' deoxyribose acted as a basal TLR9 agonist as it bound to and activated TLR9. This effect was enhanced by DNA bases, even short of CpG motifs. In contrast, PS-modified 2' deoxyribose homopolymers acted as TLR9 and TLR7 antagonists. They displayed high affinity to both TLRs and did not activate on their own, but they competitively inhibited ligand-TLR interaction and activation. Although addition of random DNA bases to the PS 2' deoxyribose backbone did not alter these effects, CpG motifs transformed TLR9-inhibitory to robust TLR9-stimulatory activity. Our results identified the PD 2' deoxyribose backbone as an important determinant of TLR9 activation by natural DNA, restrict CpG-motif dependency of TLR9 activation to synthetic PS-modified ligands, and define PS-modified 2' deoxyribose as a prime effector of TLR9 and TLR7 inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DNA, Single-Stranded / chemistry*
  • DNA, Single-Stranded / immunology*
  • Dendritic Cells / immunology
  • Deoxyribose / immunology*
  • Endosomes / immunology
  • Flow Cytometry
  • Humans
  • Male
  • Membrane Glycoproteins / immunology
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Oligonucleotides / chemistry
  • Oligonucleotides / immunology
  • Pattern Recognition, Physiological
  • Toll-Like Receptor 7 / immunology
  • Toll-Like Receptor 7 / metabolism
  • Toll-Like Receptor 9 / immunology*


  • DNA, Single-Stranded
  • Membrane Glycoproteins
  • Oligonucleotides
  • Tlr7 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Deoxyribose