Because the paper is the first report on subcellular localization of endogenous Toll-like receptor 3 (TLR3) in human dendritic cells. The concept was established by this report that TLR3 senses viral dsRNA in the endosome and induces type I interferon production by the TICAM-1 pathway. These findings of intracellular localization of TLR3 in DCs are important for anti-viral research in the fields of innate immunity and virology.

  Does it describe a new discovery, methodology, or synthesis of knowledge?

“We have succeeded in the development of function-blocking anti-human TLR3 mAb (TLR3.7).”

TLR3 expression had been analyzed only at the mRNA level until our report was published, because no anti-TLR3 mAbs capable of using in FACS analysis and immunofluorescent analysis were available. We have succeeded in the development of function-blocking anti-human TLR3 mAb (TLR3.7).

In this work, by using the mAb, we first demonstrated that virus-sensing TLR3 localizes to the intracellular compartment in human myeloid DCs but not in plasmacytoid DCs. In addition, we found that in contrast to TLR2 and TLR4 signaling, TLR3 signaling requires endosomal maturation.

  Would you summarize the significance of your paper in layman’s terms?

Among 10 TLR family members, TLR3, 7, 8, and 9 recognize virus-derived nucleic acids. Based on our findings, together with other papers on intracellular expression of TLR7, 8, and 9, it has become evident that TLRs sensing the nucleic acids all localize endosomal compartments and recognize extracellular virus-derived nucleic acids. The TLR-mediated virus detection system is completely different from the intracellular virus-sensing system, in which cytoplasmic virus sensors directly recognize intracellular virus-derived RNA/DNA.

  How did you become involved in this research and were any particular problems encountered along the way?

We are interested in the mechanisms of self-nonself discrimination by the innate immune system. Ten years ago, we started the basic study on adjuvant-mediated anti-tumor immunotherapy. We noticed that most of the adjuvant are TLR ligands and activate DCs.

In the course of the study, we found by using anti-TLR3 mAb that TLR3 recognizes dsRNA, and subsequently identified the TLR3 adaptor molecule TICAM-1 (also called TRIF). We have been working on the TLR3 study.

  Where do you see your research leading in the future?

Host virus detection systems rely on the compartmentalization of the virus-sensing receptors. We are focusing on how endosomal TLR3 functions in anti-viral immune responses.

  Are there any social or political implications for your research?

Yes, we hope so. TLR3-mediated signaling is important in the generation of adaptive immune responses through the activation of NK cells and cytotoxic T lymphocytes. Development of the effective TLR3 ligands and targeting methods to the endosomal TLR3 may be useful for adjuvant-mediated anti-tumor immunotherapy.