TLR pathways and IFN‐regulatory factors: To each its own

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Abstract
TLR trigger the induction of type I IFN (IFN‐alpha/beta), providing a crucial mechanism of anti‐viral defense. Until recently, TLR were thought to induce type I IFN responses by activating two transcription factors which belong to the IFN‐regulatory factor (IRF) family, IRF‐3 and IRF‐7. TLR‐3 and TLR‐4 induce IFN‐beta by activating IRF‐3; TLR‐9 induces IFN‐alpha and IFN‐beta through IRF‐7, at least when engaged by type A CpG oligonucleotides (CpG‐A) in plasmacytoid DC (pDC). In this issue of the European Journal of Immunology, it is demonstrated that TLR‐9 induces IFN‐beta when engaged by type B CpG oligonucleotides (CpG‐B) in myeloid DC and macrophages. Remarkably, this response is independent of IRF‐3/7 and, in fact, requires another IRF family member, IRF‐1. IRF‐1 is recruited by TLR‐9 through the adaptor MyD88. Deficiency of the TLR‐9→IRF‐1→IFN‐beta pathway results in impaired anti‐viral responses not only in vitro but also in vivo. These results demonstrate that TLR induce IFN‐alpha or IFN‐beta responses by activating distinct IRF, depending on the TLR ligand and the cell type. These distinct TLR‐IRF pathways may allow the immune system to tailor its responses to viral pathogens. See accompanying article http://dx.doi.org/10.1002/eji.200636767