image: TLR4 recognizes bacterial-derived lipopolysaccharides and activates IRF3 via the adapter protein TRIF, contributing to the induction of type I IFN genes. Within endosomes, TLR3, TLR7, and TLR9 recognize double-stranded RNA (dsRNA), single-stranded RNA (ssRNA), and hypomethylated DNA, respectively. TLR3 activates IRF3 via the adapter protein TRIF, while TLR7 and TLR9 in pDCs activate IRF7 via the MyD88 and IKK complexes. In the cytoplasm, DNA-recognizing receptors such as cGAS, DAI, IFI16, and DDX41 recognize dsDNA and activate IRF3 via the adapter protein STING on the endoplasmic reticulum or ERGIC, which in turn activates TBK1 and IKKe, leading to the induction of type I IFN genes. RLRs such as RIG-I and MDA5 recognize dsRNA and activate IRF3 and IRF7 via mitochondrial adapter proteins MAVS. Although not depicted in this figure, there is evidence that IRF5 is also involved in type I IFN gene induction in pDCs, while IRF1 contributes to the induction of type I IFNs in cDCs. There is also evidence that IRF8 is involved in the expression of type I IFN genes without its interaction with MyD88 in pDCs (see text). In the nucleus, hnRNPA2B1 recognizes DNA released by DNA viruses, forms homodimers, and is demethylated by JMJD6. Subsequently, hnRNPA2B1 translocates to the cytoplasm and activates the STING-TBK1-IRF3 pathway. IFI16 and RPSA also function as nuclear DNA sensors. Abbreviations: IRF, IFN regulatory factor; TLR, Toll-like receptor; TRIF, TIR domain-containing adapter IFN-b inducer; pDCs, plasmacytoid dendritic cells; cDCs, conventional DCs; MyD88, Myeloid differentiation primary response gene 88; TBK1, TANK-binding kinase 1; IKK, IkB kinase; RLRs, RIG-I-like receptors; cGAS, cyclic GMP-AMP synthase; STING, stimulator of IFN genes; ER, endoplasmic reticulum; ERGIC, ER-Golgi intermediate compartment; A2B1, hnRNPA2B1; JMJD6, Jumonji domain containing 6.
Credit: Professor Tadatsugu Taniguchi from The University of Tokyo, Japan Image source link: https://link.springer.com/article/10.1007/s44466-025-00019-9
Published on January 6, 2026, in Volume 2 of the Immunity & Inflammation journal, the review begins by underscoring Professor Taniguchi’s foundational role in immunology. His team's landmark discovery of IRF1 in 1988, followed by IRF2 in 1989, established an entirely new class of transcription factors central to immune regulation. To date, nine mammalian IRF members (IRF1–9) have been identified. “While sharing conserved DNA-binding and protein interaction domains, they regulate a vast spectrum of physiological and pathological processes far beyond antiviral defense, including autoimmunity, chronic inflammation, and cancer development,” the authors point out.
The review systematically details the precise activation mechanisms linking pathogen detection to IRF-driven immune responses. Upon invasion, viruses are detected by cellular pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs) and cytosolic RNA/DNA sensors. These receptors trigger distinct, complicated signaling cascades that culminate in the phosphorylation and activation of specific IRF members. This process leads to the coordinated nuclear translocation of IRFs and the robust induction of type I interferons (IFN-α/β), which in turn stimulate the expression of hundreds of interferon-stimulated genes (ISGs). This cascade forms the indispensable cornerstone of innate antiviral immunity.
The authors elaborate on the specialized and non-redundant roles of key IRF proteins. IRF1, IRF5, and IRF7 are identified as primary drivers of interferon production during viral infection. Beyond this, IRF1 plays a multifaceted role by upregulating Major Histocompatibility Complex (MHC) I molecules, thereby enhancing antigen presentation and CD8⁺ T cell activation. It also induces proteins like ZBP1, which can activate programmed cell death pathways as a direct antiviral strategy. IRF3 and IRF7 are highlighted not only for initiating responses but also for their potential role in mitigating subsequent immunopathological tissue damage. In contrast, IRF2 acts as a critical fine-tuner and negative regulator, preventing excessive and harmful inflammation by competing for DNA-binding sites and modulating promoter activity. Furthermore, IRF9 is essential for the downstream interferon response, forming the ISGF3 complex with STAT1 and STAT2 to mediate the transcription of ISGs. The review also notes the evolutionary arms race, where many viruses have developed specific virulence factors to inhibit IRF function, underscoring their pivotal role in host defense.
The authors reference the Confucian principle that "going too far is as bad as not going far enough" to illustrate the double-edged nature of IRF activity. While indispensable for host defense, persistent or aberrant activation of the IRF-interferon axis is a well-established pathogenic mechanism in autoimmune diseases such as systemic lupus erythematosus (SLE), dermatomyositis, and systemic sclerosis. The review highlights compelling genetic evidence from large-scale genome-wide association studies (GWAS), which consistently clarify specific polymorphisms in the IRF5 and IRF7 genes as major genetic risk factors for SLE. Variations in IRF3 and IRF8 are also strongly associated with disease susceptibility. This direct genetic link confirms IRFs not just as bystanders but as central therapeutic targets, making the rational design of specific IRF inhibitors a highly active and promising frontier in translational immunology.
The authors conclude, “Each IRF member performs specific but overlapping roles in immune cells, and their carefully controlled activation is essential for maintaining host homeostasis.” They propose that future research must prioritize elucidating the deep mechanistic insights, combined with innovative translational studies aimed at selectively modulating specific IRF pathways, which are essential to pave the way for novel, precise diagnostic and therapeutic strategies for a broad range of autoimmune, inflammatory, and infectious diseases.
***
Reference
DOI: 10.1007/s44466-025-00019-9
About Immunity & Inflammation
Immunity & Inflammation is a newly launched open-access journal co-published by the Chinese Society for Immunology and Springer Nature under the leadership of Editors-in-Chief Prof. Xuetao Cao and Prof. Jules A. Hoffmann. Immunity & Inflammation aims to publish major scientific questions and cutting-edge advances that explore groundbreaking discoveries and insights across the spectrum of immunity and inflammation, from basic science to translational and clinical research.
Website: https://link.springer.com/journal/44466
About Authors
Prof. Tadatsugu Taniguchi from the University of Tokyo, Japan
Prof. Tadatsugu Taniguchi is a Professor Emeritus and a Project Professor at Department of Molecular Immunology, Institute of Industrial Science, the University of Tokyo. He is a Foreign Associate Member of National Academy of Sciences (U.S.A.) and a Honorary Member of The American Association of Immunologists (U.S.A.). He pioneered the identification of key immune genes including interferon-β and interleukin-2, and discovered the IRF transcription factor family. His research focuses on signal transduction and gene expression mechanisms in immunity, inflammation, and oncogenesis.
Prof. Hideyuki Yanai from the University of Tokyo, Japan
Prof. Hideyuki Yanai is a Project Associate Professor at the Research Center for Advanced Science and Technology, the University of Tokyo, and a Professor at the Department of Cancer Biology, Yokohama City University Graduate School of Medicine. His research focuses on innate immunity and inflammation.
Funding information
This work was supported in part by Grant-In-Aid for Scientific Research (24H00606 to T.T), the Takeda Science Foundation (to H.Y.), Astellas Foundation for Research on Metabolic Disorders (to H.Y.), Daiichi Sankyo Foundation of Life Science (to H.Y.), and Chugai Foundation for Innovative Drug Discovery Science (to H.Y.). The Department of inflammology is supported by Boostimmune Inc.
Method of Research
Systematic review
Subject of Research
Not applicable
Article Title
The IRF transcription factor family in type I interferon-mediated antiviral immunity and associated diseases
Article Publication Date
6-Jan-2026
COI Statement
The corresponding author Tadatsugu Taniguchi is the Associate Editor of this journal Immunity & Inflammation. However, he was not involved in the peer-review or decision-making process for this manuscript. The authors declare no other competing interests.