Immunology Select

In our Select pages, we highlight exciting themes that emerge from our review of the recent literature. In this issue's Immunology Select, we discuss a cluster of recent papers that further our understanding of the host innate immune response to viruses and provide an example of the evasion of the immune response by a viral protein. The innate immune response is an early line of defense against invading pathogens. This response is mediated largely by members of the Toll-like receptor (TLR) family, which depend on adaptor proteins, such as MyD88 and TRIF, to mediate downstream signaling events. Activation of TLRs culminates in the activation of transcription factors , such as NF-kB and IRF3, that induce production of both pro-and anti-inflammatory cytokines and interferons (IFNs) by macrophages and dendritic cells. Different TLRs respond to different molecules, for example, TLR4 recognizes lipopolysaccharide (a component of the cell wall of Gram negative bacteria; LPS) and TLR3 recognizes the double-stranded (ds)RNA genome of viruses. Elucidating the function of the adaptor proteins downstream of TLRs is crucial for deciphering the specificity of the innate immune response. Oganesyan et al. now characterize the adaptor protein TRAF3. They show that this protein is unexpectedly a key molecule in both the TLR-dependent and TLR-independent production of type I IFNs. The authors first tested the involvement of TRAF3 in TLR signaling by stimulating macrophages from mouse bone marrow that lack TRAF3 with a synthetic dsRNA or LPS (agonists for TLR3 and TLR4, respectively). They found reduced expression of the gene that encodes IFN-b in these macrophages indicating that TRAF3 is downstream of both TLR3 and TLR4. The authors show that TRAF3 is important for TLR3-mediated inhibition of the replication of murine g-herpes virus 68 and vesicular stomatitis virus (VSV) indicating that this adaptor protein is involved in the antiviral response. As the TRIF adaptor protein is crucial for TLR3-and TLR4-dependent IFN production, the authors examined whether there was a connection between TRIF and TRAF3. Indeed , TRAF3 associates with TRIF and its downstream effector kinases TBK1 and IKK-3, and enhanced the ability of these proteins to activate the Ifnb promoter. TRAF3 is also important for the nuclear localization of the transcription factor IRF3, which modulates expression of the gene encoding IFN-b. Therefore, TRAF3 is a critical adaptor protein for TRIF-mediated activation of IRF3 and for IFN-b production. The authors also show that TRAF3 is involved in the production of …