| The study of innate immunity has been revolutionized in recent years by discovery of the major role played by Toll-like receptors (TLR) in pathogen recognition and immune activation. Evolutionarily conserved from flies to humans, TLRs signal the presence of conserved microbial signatures. To date, eleven mammalian TLRs have been discovered. TLR signaling leads to production of proinflammatory and immunoregulatory cytokines and the maturation of dendritic cells. Although the activation of innate immune responses through TLRs is necessary for survival, overactivation of such responses can be deleterious. Thus, TLR-mediated responses demand tight regulation. The paradigmatic bacterial activator of innate immune responses, lipopolysaccharide, signals through TLR4. RP105 is a TLR4 homolog, thought to be largely B cell-specific, which lacks a signaling domain. We report that the distribution of RP105 expression is wide, directly mirroring that of TLR4 on antigen presenting cells. We further show that RP105 is a specific inhibitor of TLR4 signaling in HEK293 cells, a function conferred by its extracellular domain. Notably, RP105 and its helper molecule, MD-1, interact directly with the TLR4 signaling complex, inhibiting its ability to bind microbial ligand. We further demonstrate that RP105 regulates TLR4 signaling in primary dendritic cells and macrophages in vitro . Finally, we show that RP105 modulates responses to LPS in vivo, as well as in in vitro and in vivo immune responses to infection with the protozoan parasite, L. major. These results identify RP105 as a physiological negative regulator of TLR4 signaling. |
