The signaling pathways via Toll-like receptors (TLRs) are regulated by selective usage of adaptor molecules that are recruited to the cytoplasmic portion of individual TLRs after ligand stimulation. These adaptors include MyD88, TRIF, TIRAP/Mal and TRAM. The TLR signaling is largely composed of MyD88-dependent and TRIF-dependent pathways. The MyD88-dependent pathway is essential for inflammatory cytokine production, while the TRIF dependent pathway is involved in type 1 interferon production through activation of transcription factor, IRF3. Stimulation of TLR3, TLR4, TLR7, and TLR9 induces type 1 interferon. TLR3- or TLR4-mediated type 1 interferon production is shown to be regulated by the TRIF-dependent pathway in a variety of cell types. In contrast, TLR7- or TLR9-dependent type 1 interferon production is dependent on MyD88, and is confined to a specific subset of dendritic cells, so-called plasmacytoid dendritic cells (PDC). The molecular mechanism of such MyD88-dependent type 1 interferon production was unknown. This is the first paper that provides a clue to the mechanism on type I interferon induction of PDC in response to viral infection.

It describes that the formation of a complex consisting of adapters MyD88, TRAF6, and a transcription factor IRF7 is responsible for the type I interferon induction by viral single stranded RNA (TLR7-ligand) and DNA (TLR9-ligand) in pDC. The exploitation of drugs that activate or block this pathway will be useful in the treatment of various diseases caused by viral infection and autoimmune diseases such as systemic lupus erythematosus.

In response to viral infection, host cells release an antiviral factor—namely, interferon. Viral components such as single-stranded RNA and DNA are recognized by specific sensors called TLR7 and TLR9, respectively, which are expressed on host immune cells. We demonstrated that the induction of interferon by TLR7 or TLR9 is mediated through activation of a unique intracellular signaling pathway.

We have been interested in how innate immune cells recognize microbial pathogens to induce inflammatory responses as well as develop adaptive immunity. Since 1998, when we discovered that MyD88 knockout mice are unresponsive to many microbial components with immunostimulatory activity, we have investigated the roles of TLR family members and their signaling pathways in innate immune system.