New vistas on TLR9 activation

Together with other reports, evidence published in this issue of the European Journal of Immunology by Avalos and Ploegh (Eur. J. Immunol. 2011. 41: 2820-2827) implies that trafficking of TLR9 from the ER to endolysosomal compartments, which is aided by the transmembrane UNC93B1 ER protein, is followed by proteolytic cleavage of the TLR9 ectodomain (TLR9ecto). Furthermore, Avalos and Ploegh elegantly show that RAW 264.7 macrophages stably expressing tagged TLR9 display significant amounts of cleaved TLR9 already when at rest. It is of note that inhibitory oligonucleotides (IN-ODNs) do not affect TLR9 cleavage but competitively prevent CpG-ligand binding to the C-terminal TLR9 fragment. Compared with phosphorothioated (PS) CpG-oligodeoxynucleotides (ODNs), natural phosphorodiester (PD) CpG-ODNs differ in their TLR9 activation efficiency. In this Commentary, a model is proposed that accounts for the differences in PS-and PD-ODNs with respect to TLR binding and activation.