This is the first paper that described the molecular mechanisms by which synthetic antiviral compounds exert their activities on mammalian immune cells. One of the imidazoquinolines, imiquimod, is now used for treatment of genital warts caused by human papillomavirus in the clinic; however, how this compound activates immune function remained unclear. Our paper clearly demonstrates that imidazoquinolines activate immune cells by means of the TLR7 signaling pathway, and leads to induction of interferon-alpha and other inflammatory cytokines. The toll-like receptor (TLR) family plays a critical role in the recognition of invading microbes within the host and controls immune responses. Activation of the receptors is now considered to be promising for the development of drugs that trigger antibacterial, antifungal, and antiviral responses in the body. Therefore, we think this is why our paper dealing with the identification of TLR7 ligand is highly cited.

The ligand for TLR7 was not known at that time. Although the natural ligand(s) for TLR7 are still unknown, identification of TLR7 ligands definitely brought us closer to studies on the functional role of this receptor as well as the signaling pathways activated through it.

TLRs recognize microbial components contained in vaccine adjuvants, indicating that they act as adjuvant receptors to control innate and adaptive immune responses. Our paper demonstrated that the synthetic chemical compounds exert anti-tumor and anti-viral effects through the adjuvant action. The future design of antiviral compounds based on TLR7 ligands should be more facilitated. Our paper also suggests a possibility that some viral component might activate the immune cells through TLR7, and therefore TLR7 might be a detector of viral invasion in the body.

We were interested in the function of TLRs and have shown that they can recognize some bacterial components and activate innate and adaptive immunity. However, the physiological role of TLR7 remained unclear. To clarify this question, we generated by gene-targeting strategy the mice lacking MyD88, an adaptor protein essential for cytokine production via all TLR ligands. The MyD88-deficient cells did not show any response to the imidazoquinolines. Therefore, we speculated that the compounds activate immune cells through TLRs, and analyzed TLR7-deficient mice and cells.