IRF-7 is the master regulator of type-I interferon-dependent immune responses

Abstract

The type-I interferon (IFN-alpha/beta) response is critical to immunity against viruses and can be triggered in many cell types by cytosolic detection of viral infection, or in differentiated plasmacytoid dendritic cells by the Toll-like receptor 9 (TLR9) subfamily, which generates signals via the adaptor MyD88 to elicit robust IFN induction. Using mice deficient in the Irf7 gene (Irf7-/- mice), we show that the transcription factor IRF-7 is essential for the induction of IFN-alpha/beta genes via the virus-activated, MyD88-independent pathway and the TLR-activated, MyD88-dependent pathway. Viral induction of MyD88-independent IFN-alpha/beta genes is severely impaired in Irf7-/- fibroblasts. Consistently, Irf7-/- mice are more vulnerable than Myd88-/- mice to viral infection, and this correlates with a marked decrease in serum IFN levels, indicating the importance of the IRF-7-dependent induction of systemic IFN responses for innate antiviral immunity. Furthermore, robust induction of IFN production by activation of the TLR9 subfamily in plasmacytoid dendritic cells is entirely dependent on IRF-7, and this MyD88-IRF-7 pathway governs the induction of CD8+ T-cell responses. Thus, all elements of IFN responses, whether the systemic production of IFN in innate immunity or the local action of IFN from plasmacytoid dendritic cells in adaptive immunity, are under the control of IRF-7.

Endoplasmic reticulum stress and the unfolded protein response are linked to synergistic IFN‐β induction via X‐box binding protein 1

“…TLR9 agonists (e.g. type B CpG DNA) stimulate robust IFN-b induction in myeloid DC and macrophages through MyD88 and IRF-1 independently of IRF3 or IRF7 [12,41]. Lack of synergy with the TLR9 agonist is consistent with specificity of IFN-b synergy for the IRF3 activating pathways.…”

TLR signalling and activation of IRFs: revisiting old friends from the NF-κB pathway

“…Thus, in plasmacytoid DCs, IRF7 is the key regulator of type I IFN production. This has been confirmed recently with the generation of mice deficient in the Irf7 gene [60]. Plasmacytoid DCs derived from these mice are completely non-responsive to TLR7 and TLR9 ligands with respect to induction of IFN-a, whereas induction is normal in plasmacytoid DCs from IRF3-deficient mice.…”

Gene structures and promoter characteristics of interferon regulatory factor 1 (IRF-1), IRF-2 and IRF-7 from snakehead Channa argus

“…CaIRF-7 should have different recognition motifs because two of six tryptophans are substituted in IRF-7 compared with CaIRF-1 and CaIRF-2. Though human IRF-7 is found as multiple forms (Lin et al, 2000;Honda et al, 2005), splicing variant of IRF-7 have not been found and isolated in teleosts.…”

“…According to IRF-1 and IRF-2 crystal structure in mouse (Escalante et al, 1998;Fujii et al, 1999), tertiary structures of predicted CaIRF-1 and CaIRF-2 DBD models consist of three ␣-helixes (␣1-␣3) with four stranded ␤-sheets (␤1-␤4) and three long loops (L1-L3), suggesting that these consistent elements should have uniform functions and recognize similar sequences. There is a lack of knowledge in teleosts with respect to IRF-7 which is the master regulator of type I IFN-dependent immune responses in mammals (Honda et al, 2005). CaIRF-7 gene consists of 10 exons and 9 introns, and lacks intron in 5 UTR that presents to human IRF-7a gene.…”