An Essential Role for the N-terminal Fragment of Toll-like Receptor 9 in DNA Sensing

Nat Commun. 2013;4:1949. doi: 10.1038/ncomms2949.

Abstract

Toll-like receptor 9 (TLR9) is an innate immune sensor for microbial DNA that erroneously responds to self DNA in autoimmune disease. To prevent autoimmune responses, Toll-like receptor 9 is excluded from the cell surface and silenced until the N-terminal half of the ectodomain (TLR9N) is cleaved off in the endolysosome. Truncated Toll-like receptor 9 (TLR9C) senses ingested microbial DNA, although the precise role of the truncation remains controversial. Here we show that TLR9 is expressed on the surface of splenic dendritic cells. Following the cleavage of TLR9 in the endolysosome, N-terminal half of the ectodomain remains associated with truncated TLR9, forming the complex TLR9N+C. The TLR9-dependent cytokine production by Tlr9(-/-) dendritic cells is rescued by a combination of TLR9N and TLR9C, but not by TLR9C alone. These results demonstrate that the TLR9N+C complex is a bona fide DNA sensor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibody Specificity / immunology
  • Bone Marrow Cells / cytology
  • Cell Membrane / metabolism
  • Cytokines / biosynthesis
  • DNA / immunology
  • DNA / metabolism*
  • Dendritic Cells / metabolism
  • Humans
  • Lysosomes / metabolism
  • Mice
  • Molecular Sequence Data
  • Protein Binding
  • Proteins / metabolism
  • Signal Transduction
  • Spleen / cytology
  • Structure-Activity Relationship
  • Toll-Like Receptor 9 / chemistry*
  • Toll-Like Receptor 9 / deficiency
  • Toll-Like Receptor 9 / immunology
  • Toll-Like Receptor 9 / metabolism*
  • Transduction, Genetic

Substances

  • Antibodies, Monoclonal
  • Cytokines
  • Proteins
  • Toll-Like Receptor 9
  • leucine-rich repeat proteins
  • DNA