“Until TLR ligands were identified, the response to all TLR ligands was considered to be identical and entirely dependent on MyD88.”

Toll-like receptors (TLRs) play a critical role in the sensing of invading pathogens, and subsequent inflammatory and immune responses to eradiate the pathogens. The identification of TLRs in mammals has led to a reappraisal of innate immunity that was originally appreciated by the Russian zoologist and microbiologist Élie Metchnikoff—he shared the 1908 Nobel Prize in Physiology or Medicine with Paul Ehrlich for his discovery in animals of amoeba-like cells that engulf foreign bodies such as bacteria—but this idea later had been discarded as a non-specific response and this opinion held on for some time in the field of immunology. Until recently, more emphasis had been placed on the study of acquired immunity. However, recent studies have shown that innate immunity is, in fact, not non-specific but specific enough to discriminate self and pathogens through evolutionarily conserved receptors, named Toll-like receptors (TLRs), which play a crucial role in early host defense against invading pathogens. More importantly, it has been shown that activation of innate immunity is a prerequisite to induction of acquired immunity. This paradigm shift is now changing our thinking on pathogenesis and the treatment of infectious diseases, immune and allergic diseases, and cancers. Thus, many researchers in the field of immunology as well as microbiology are now devoting much more attention to the progress in TLR research. Our review article is an updated one by experts, and particularly focuses on the recent progress in the TLR signaling. We think that the high citation rate should reflect the evaluation of our leading contribution to the clarification of TLR signaling pathways.

The involvement in this research started with our generation of mice lacking MyD88, an adaptor molecule for IL-1 signaling. We found that MyD88 KO mice were unresponsive to LPS in addition to IL-1. This finding indicated that the LPS signaling receptor uses MyD88 as an adaptor. At the same time, the existence of TLRs in mammals was reported by other groups. The TLR family harbors an extracellular leucine-rich repeat (LRR) domain as well as a cytoplasmic domain that is homologous to that of the IL-1R family. We imagined that a member of Toll-like receptors would be a candidate of LPS receptor. We searched in the database and found several unpublished TLR members and started to knockout all of the TLR family members. Although the publication on TLR4 as LPS receptor was slightly behind the seminal finding of Bruce Beutler of the Scripps Institute with LPS unresponsive natural mutant mice, we took advantage of the identification of ligands of other members because of a full stock of TLR knockout mice.

Until TLR ligands were identified, the response to all TLR ligands was considered to be identical and entirely dependent on MyD88. However, our group has shown for the first time that the signaling pathway through TLRs differs from each other, thereby resulting in different gene expression and biological responses. In addition to MyD88, several MyD88-related adaptor proteins were identified in the database. The generation of individual adaptor molecules showed that the difference among TLR responses is in part due to differential utilization of adaptor molecules.