One of the recent advances in immunology is the discovery and elucidation of Toll-like receptor (TLR) family members. TLRs have been shown to recognize microbial components such as LPS, peptidoglycan, and double-stranded RNA (dsRNA) and trigger cellular immune responses, including proinflammatory cytokine production. Cytoplasmic regions of all of TLRs resemble those of Interleukin (IL)-1 receptor family members—called the Toll/IL-1R (TIR) domain. An intracellular adaptor protein, MyD88, has been shown to associate with the TIR domain of TLRs, transduce the signal downstream to the nucleus. MyD88-deficient mice showed defective cytokine production in response to IL-1 and TLR ligands, except for dsRNA which is recognized by TLR3. The signaling cascade activated by TLR3 is reportedly independent on MyD88, and leads to induction of type I interferon (IFN) and IFN-inducible genes. The TLR4 ligands, LPS, also stimulates induction of IFN-beta in the absence of MyD88, indicating that TLR3 and TLR4 signaling cascades possess the MyD88-independent pathway. Our paper deciphers the MyD88-independent pathway through the identification and characterization of a new TIR domain-containing adaptor molecule named TRIF (TIR domain-containing adaptor inducing IFN-beta). In the paper, we demonstrated that overexpression of TRIF-induced activation of the IFN-beta promoter, and TRIF interacted with TLR3 and downstream molecules.

We think this is the first study that provides a clue to understanding the missing puzzle of the MyD88-independent pathway.

In viral infection, the human body generates an anti-viral protein called interferon. A viral component, dsRNA, strongly induces interferon through the recognition by TLR3 and signal transduction by TRIF. Detailed understanding how TRIF acts in the TLR3 signaling cascade is crucial for the design of effective drugs to use against viruses.

Masahiro Yamamoto
Department of Host Defense
Research Institute for Microbial Diseases
Osaka University
Osaka, Japan