Friday, October 28, 2011
Room A2/A7 (San Jose Convention Center)
Recognition of nucleic acids as a signature of infection by Toll-like receptors (TLRs) 7 and 9
exposes the host to potential self-recognition and autoimmunity. It has been proposed that
intracellular compartmentalization is largely responsible for reliable self/non-self discrimination
by these receptors. We have previously shown that TLR9 and TLR7 require processing prior to
activation, which may further restrict receptor compartmentalization and reinforce self/non-self
discrimination, yet this possibility remains untested. Here we report that residues within the
TLR9 transmembrane (TM) region confer the requirement for ectodomain proteolysis. TLR9
TM mutants responded to extracellular DNA and mice expressing such receptors died from
systemic inflammation and anemia. This inflammatory disease did not require lymphocytes and
appears to require recognition of self-DNA by dendritic cells. These results provide the first
demonstration that TLR-intrinsic mutations can lead to a break in tolerance and support the
hypothesis that ectodomain processing has evolved to reinforce self/non-self discrimination by
nucleic acid-sensing TLRs.
exposes the host to potential self-recognition and autoimmunity. It has been proposed that
intracellular compartmentalization is largely responsible for reliable self/non-self discrimination
by these receptors. We have previously shown that TLR9 and TLR7 require processing prior to
activation, which may further restrict receptor compartmentalization and reinforce self/non-self
discrimination, yet this possibility remains untested. Here we report that residues within the
TLR9 transmembrane (TM) region confer the requirement for ectodomain proteolysis. TLR9
TM mutants responded to extracellular DNA and mice expressing such receptors died from
systemic inflammation and anemia. This inflammatory disease did not require lymphocytes and
appears to require recognition of self-DNA by dendritic cells. These results provide the first
demonstration that TLR-intrinsic mutations can lead to a break in tolerance and support the
hypothesis that ectodomain processing has evolved to reinforce self/non-self discrimination by
nucleic acid-sensing TLRs.