Heat shock proteins as ligands of toll-like receptors.

Toll-like receptors (TLRs) have been described as sensors for pathogen-associated molecular patterns crucial for the initiation of an innate immune response. These mechanisms were developed long before the adaptive immune system evolved. The latest additions to the growing list of TLR ligands are heat shock proteins (HSPs). Interestingly, not only bacterial but also mammalian HSPs interact with TLRs demonstrating that the exclusive association of TLRs with microbial ligands is obsolete. Human HSP60 and Gp96 are the first examples of non-pathogen derived ligands of TLRs. More importantly, Gp96 provides the first example of how the innate and adaptive immune system can be stimulated simultaneously by the same molecule which is released under physiological conditions from necrotic cells. Understanding the mechanisms of innate immune system interaction with HSPs will make it possible to rationally modulate immune responses, either towards immunity or towards tolerance.