ABSTRACT
We discuss why evolutionary pressure may have exiled nucleic acid sensing TLRs (TLR3, TLR7/8, and TLR9) to endosomal compartments of immune cells. This expression pattern contrasts with that of TLR1, 2, 4, 15, and 6 and TLR5 known to be anchored on the cell surface. We argue that cell-surface expressed TLRs primarily recognize unique and conserved pathogen-derived structures such as endotoxin that are not present in the host. Thus, a failure of self/non-self discrimination is less probable. Conversely, structural differences among pathogen-derived versus hostderived nucleotides are not as stringent as to exclude the potential for self reactivity. Specifically, we review experimental conditions under which self DNA and singlestranded (ss) DNA devoid of any CpG motifs activate TLR9. The type of endosomal of DNA in plasmacytoid dendritic cells (PDCs) trafficking (early versus late endosomes) rather than the DNA sequence itself determines the type of cytokines produced (type I interferons versus pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α and interleukin (IL)-12). Since enforced endosomal translocation of host (self) DNA activates TLR9, it appears that under homeostatic conditions the poor endosomal translocation of self DNA represents a major control mechanism for self versus non-self (pathogen) DNA discrimination.
