UC Berkeley

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. Our lab has previously shown that TLR9 and TLR7 require processing prior to activation, which may further restrict TLR9 and TLR7 compartmentalization and reinforce self/non-self discrimination; although, this possibility has remained untested. We have identified residues within the TLR9 transmembrane (TM) region that 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.