Affinage

IRF4

Interferon regulatory factor 4 · UniProt Q15306

Length
451 aa
Mass
51.8 kDa
Annotated
2026-04-28
100 papers in source corpus 39 papers cited in narrative 40 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

IRF4 is a lymphoid-enriched transcription factor that functions as a concentration-dependent, cofactor-determined regulator of immune cell fate decisions across B cells, T cells, dendritic cells, macrophages, and NK cells. At low concentrations, IRF4 binds high-affinity ISRE and EICE composite elements cooperatively with partners such as PU.1, SPIB, or Ikaros to support germinal center formation and Tfh fate, whereas at high concentrations—driven by TCR/BCR signal strength via the ITK-Ras pathway—it occupies low-affinity AICE sites with BATF to drive plasma cell differentiation (upstream of Blimp-1 and XBP-1), CD8+ effector programs, Th9/Tr1 differentiation, and T cell exhaustion (PMID:28930660, PMID:16767092, PMID:24531538, PMID:29246443, PMID:24875472, PMID:29670755). Crystal structures reveal that IRF4 homodimers assemble on ISRE DNA through protein–DNA contacts without protein–protein interfaces, while heterodimeric complexes with PU.1 involve direct protein–protein interaction, and disease-associated mutations (T95R, C99R, L116R) alter binding specificity to produce multimorphic transcriptional outcomes including autosomal dominant combined immunodeficiency and Hodgkin lymphoma pathogenesis (PMID:33533913, PMID:36662884, PMID:37935654). Beyond the immune system, IRF4 partners with PGC-1α in brown adipocytes to drive thermogenic gene expression, controls skeletal muscle glycogen through PTG regulation, and promotes hepatic steatosis via transcriptional induction of FSTL1, while its activity is modulated post-translationally by IRAK4-mediated phosphorylation and RNF2-mediated ubiquitin-proteasomal degradation and epigenetically through JMJD3-dependent histone demethylation and METTL3-dependent m6A modification of its mRNA (PMID:24995979, PMID:33042761, PMID:37770480, PMID:35443173, PMID:34670117).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1995 High

    The foundational question of whether a lymphoid-restricted IRF family member existed was answered by the cloning of IRF4/LSIRF, establishing that it binds ISRE motifs and is induced by antigen receptor signaling rather than interferons, distinguishing it from classical IRFs.

    Evidence Molecular cloning, in vitro DNA binding, and expression profiling in lymphoid cells

    PMID:7541907

    Open questions at the time
    • No in vivo function established
    • No partner dependency characterized
    • Mechanism of antigen-receptor-dependent induction unknown
  2. 1996 High

    Whether IRF4 activates or represses IFN-responsive genes was resolved: IRF4 acts as a transcriptional repressor of interferon-regulated promoters, with target selectivity distinct from IRF-2 and ICSBP.

    Evidence Cotransfection reporter assays with multiple ICS sequences in human embryonal carcinoma cells

    PMID:8657101

    Open questions at the time
    • Repression mechanism not defined (corepressor recruitment unknown)
    • Physiological relevance of repression in lymphoid cells not tested
  3. 1997 High

    The question of whether IRF4 has oncogenic relevance was answered by the discovery that the t(6;14) translocation in multiple myeloma deregulates IRF4 via IgH juxtaposition, and IRF4 exhibits oncogenic activity in vitro.

    Evidence Chromosomal breakpoint cloning, FISH, mRNA expression, and in vitro transformation assay

    PMID:9326949

    Open questions at the time
    • Downstream oncogenic targets not identified
    • Whether IRF4 is sufficient for myelomagenesis in vivo unknown
  4. 1998 High

    How IRF4 achieves target specificity despite weak intrinsic DNA affinity was explained by structural and biochemical evidence that PU.1 and IRF4 form a cooperative ternary complex on immunoglobulin enhancer elements, with IRF4 residues 1–19 paradoxically reducing its own affinity while enhancing cooperative binding.

    Evidence Fluorescence polarization DNA binding assays, domain mapping, and NMR spectroscopy

    PMID:9642085

    Open questions at the time
    • No structure of the ternary complex
    • Whether other IRF members share this cooperative mechanism unknown
  5. 2006 High

    The central in vivo question—what IRF4 does in B cell biology—was resolved: IRF4 is required for plasma cell differentiation and class-switch recombination, acting upstream of Blimp-1 and XBP-1 to drive germinal center exit.

    Evidence Conditional Irf4 knockout in GC B cells with immunological phenotyping in transgenic mice

    PMID:16767092

    Open questions at the time
    • Dose-dependent vs. binary requirement not distinguished
    • Direct transcriptional targets not mapped genome-wide
  6. 2014 High

    Multiple studies collectively established that IRF4 functions as a quantitative interpreter of antigen receptor signal strength across multiple lymphocyte lineages: low IRF4 concentrations favor GC/Tfh fate via high-affinity site occupancy, while high concentrations (driven by ITK-Ras signaling) occupy low-affinity AICE sites with BATF to drive effector fate, plasma cell differentiation, and sustained CD8+ T cell responses.

    Evidence ChIP-seq with graded IRF4 expression, Irf4-/- mice in LCMV infection, conditional deletion in B cells and DCs, genetic fate-mapping

    PMID:24489086 PMID:24531538 PMID:24591370 PMID:28930660

    Open questions at the time
    • How IRF4 protein levels are quantitatively decoded at the chromatin level remains incompletely understood
    • Whether concentration-dependent binding applies equally in all cell types not tested
  7. 2014 High

    Outside the immune system, IRF4 was discovered as a metabolic transcription factor: it partners with PGC-1α in brown adipocytes to drive thermogenic gene expression, with knockout causing obesity and cold intolerance.

    Evidence Adipocyte-specific IRF4 KO and OE, Co-IP of IRF4–PGC-1α, metabolic phenotyping

    PMID:24995979

    Open questions at the time
    • Whether IRF4 binds PGC-1α directly or through a bridging factor not resolved structurally
    • Upstream signals controlling IRF4 in adipocytes beyond cAMP not fully defined
  8. 2016 High

    How IRF4 connects to innate immune polarization was established: IRF4 is required for M2 macrophage activation downstream of converging mTORC2 and IL-4R/Stat6 pathways, linking IRF4 to metabolic reprogramming (glycolysis) in macrophages.

    Evidence Rictor-KO macrophages, IL-4 stimulation, metabolic and gene expression assays

    PMID:27760338

    Open questions at the time
    • Direct IRF4 targets controlling glycolytic gene expression not identified
    • Whether IRF4 is phosphorylated by mTORC2 not tested
  9. 2017 High

    The mechanism by which IRF4 regulates T cell exhaustion was delineated: high TCR-induced IRF4 with BATF and NFATc1 drives exhaustion markers (PD-1) and metabolic impairment during chronic infection, while IRF4 also represses chromatin accessibility at PD-1 regulatory elements through restriction of Helios binding.

    Evidence Chronic vs. acute LCMV infection with genetic reduction of IRF4; ATAC-seq and Helios ChIP in T cell-specific IRF4 KO

    PMID:29221730 PMID:29246443

    Open questions at the time
    • Apparent paradox between IRF4 promoting and repressing PD-1 in different contexts not fully reconciled
    • Whether exhaustion reversal by IRF4 reduction is therapeutically achievable long-term unknown
  10. 2018 High

    Genome-wide studies resolved how IRF4 achieves cell-type-specific binding: in ABC-DLBCL, SPIB is the dominant cofactor redirecting IRF4 to SPIB-dependent sites, while in plasma cells, Ikaros heterodimerizes with IRF4 at ZICE elements for repression (e.g., Ebf1) and at EICEs with PU.1 for activation.

    Evidence ChIP-seq for IRF4/SPIB/PU.1/BATF with SPIB knockdown; IRF4 ChIP-seq with Ikaros KO in plasma cells, Co-IP

    PMID:24875472 PMID:29669755

    Open questions at the time
    • Complete catalog of composite elements and cofactor combinations not yet established
    • Whether SPIB-IRF4 interaction is direct or chromatin-mediated not structurally resolved
  11. 2021 High

    The structural basis for IRF4 homodimeric versus heterodimeric DNA recognition was resolved by crystallography: homodimers form exclusively through protein–DNA contacts with DNA deformation, while heterodimers with PU.1 involve direct protein–protein contacts, and disease mutations (L116R in CLL) enhance DNA binding.

    Evidence X-ray crystallography of IRF4/ISRE homodimeric complex, mutagenesis, comparison with heterodimer structure

    PMID:33533913

    Open questions at the time
    • No structure of full-length IRF4 or IRF4-BATF complex
    • How DNA deformation contributes to target selectivity in vivo not tested
  12. 2021 High

    The BATF-IRF4 interaction was shown to be directly required for countering T cell exhaustion in CAR T cells in vivo, using a BATF mutant unable to interact with IRF4 that failed to rescue antitumor function.

    Evidence CAR T cell tumor models with BATF overexpression vs. IRF4-interaction-deficient BATF mutant

    PMID:34282330

    Open questions at the time
    • Structural basis of BATF-IRF4 interaction not defined
    • Whether other AP-1 family members can substitute for BATF unknown
  13. 2023 High

    The pathological consequences of altered IRF4 DNA-binding were defined by two disease-causing mutations: T95R causes autosomal dominant combined immunodeficiency through simultaneous hypermorph/hypomorph/neomorph activity, while C99R in Hodgkin lymphoma abolishes canonical IRF binding and creates neomorphic AICE occupancy blocking plasma cell differentiation.

    Evidence Patient genetics with knock-in mouse models, ChIP-seq comparing WT vs. mutant, binding assays, transcriptome profiling

    PMID:36662884 PMID:37935654

    Open questions at the time
    • Whether other IRF4 DBD mutations produce similar multimorphic behaviors not systematically surveyed
    • Therapeutic approaches to counter neomorphic binding not developed
  14. 2023 High

    IRF4's metabolic roles were extended to skeletal muscle (controlling glycogen via PTG) and inter-organ communication (driving hepatic steatosis via FSTL1 secretion), and to NK cell biology where it serves as a metabolic checkpoint for virus-specific expansion.

    Evidence Muscle-specific IRF4 KO/OE with PTG rescue; NASH diet model with FSTL1 rescue; NK cell-specific IRF4 KO in MCMV infection

    PMID:33042761 PMID:37697097 PMID:37770480

    Open questions at the time
    • Whether IRF4's metabolic checkpoint role in NK cells mirrors its mechanism in T cells not determined
    • Direct IRF4 binding sites at PTG and FSTL1 loci not mapped by ChIP
  15. 2024 High

    The chromatin remodeling dependency of IRF4 function was established: ARID1A (SWI/SNF) is required for IRF4 expression and physically associates with IRF4 on chromatin in myeloma, while METTL3 promotes IRF4 expression via m6A modification of its mRNA in SLE B cells.

    Evidence Functional genomics, spatial proteomics, ChIP-seq/ATAC-seq with Arid1a KO in B cells; MeRIP-seq with AAV-mediated METTL3 OE/IRF4 KD in MRL/lpr mice

    PMID:38906156 PMID:39501302

    Open questions at the time
    • Whether ARID1A-IRF4 interaction is direct or bridged by other SWI/SNF subunits unknown
    • Whether m6A-mediated IRF4 regulation operates in normal B cell biology not tested
    • Full spectrum of post-transcriptional IRF4 regulation not defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include how IRF4's apparently opposing roles (promoting vs. repressing PD-1/exhaustion in different contexts) are mechanistically reconciled, the complete structural basis for IRF4-BATF and IRF4-SPIB complexes on DNA, and whether concentration-dependent binding site selection operates uniformly across all IRF4-expressing cell types.
  • No crystal structure of IRF4-BATF or IRF4-SPIB complexes
  • Context-dependent opposing roles in T cell exhaustion not mechanistically unified
  • Systematic dose-response mapping of IRF4 binding across cell types lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 9 GO:0003677 DNA binding 6
Localization
GO:0005634 nucleus 3
Pathway
R-HSA-1643685 Disease 7 R-HSA-74160 Gene expression (Transcription) 7 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3
Partners
ARID1ABATFIKZF1PGC1APU.1RNF2SMAD2SPIB
Complex memberships
IRF4-BATF heterodimerIRF4-Ikaros heterodimerIRF4-PU.1 ternary complexMyddosome (MyD88/IRAK4/IRF4)

Evidence

Reading pass · 40 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 IRF4 (LSIRF) was identified as a lymphoid-specific transcription factor that binds to the interferon-stimulated response element (ISRE) of the MHC class I promoter. Its expression is induced by antigen-receptor-mediated stimuli (lectin, CD3, IgM crosslinking) but not by interferons. Molecular cloning, in vitro DNA binding studies, expression profiling in lymphoid cells Nucleic acids research High 7541907
1996 IRF4 (ICSAT) acts as a transcriptional repressor of interferon-regulated genes, with differential repressive effects from other IRF repressors (IRF-2, ICSBP) on different IFN-responsive promoters. Repressive function demonstrated by cotransfection in human embryonal carcinoma cells. Cotransfection reporter assay, in vitro DNA binding with four different ICS sequences Molecular and cellular biology High 8657101
1997 IRF4 (MUM1) is deregulated in multiple myeloma by the t(6;14)(p25;q32) chromosomal translocation that juxtaposes IRF4 to the IgH locus, causing IRF4 overexpression; IRF4 has oncogenic activity in vitro. Chromosomal breakpoint cloning, FISH, mRNA expression analysis, in vitro oncogenicity assay Nature genetics High 9326949
1998 The DNA-binding domains of PU.1 and IRF4 form a cooperative ternary complex on immunoglobulin enhancer elements (lambdaB, kappaE3' sites). IRF4 residues 1–19 reduce its own DNA-binding affinity but enhance cooperative binding with PU.1. The cooperative interaction depends on proper spacing of binding sites but not on phosphorylation of PU.1's PEST domain. NMR showed residues 1–19 of IRF4 and the PEST domain of PU.1 are unstructured in isolation. Fluorescence polarization DNA binding assay, domain mapping, NMR spectroscopy Journal of molecular biology High 9642085
2006 IRF4 is required for plasma cell differentiation and class-switch recombination in germinal center B cells. Conditional deletion of Irf4 in GC B cells abolished post-GC plasma cells, memory B cell-to-plasma cell differentiation, AID expression, and CSR. IRF4 acts upstream of Blimp-1 and XBP-1 in the plasma cell differentiation pathway. Conditional knockout (Cre-lox), genetic epistasis, immunological assays in transgenic mice Nature immunology High 16767092
2010 IRF4 is required for plasma cell differentiation and acts as part of the BLIMP1-IRF4-XBP1 transcriptional triad; IRF4 promotes germinal center exit, Ig class switch recombination, and plasma cell identity while being absent from GC B cells. Review synthesizing conditional KO studies and gene expression analyses Immunological reviews Medium 22500833
2013 Smad2/3 and IRF4 physically interact and cooperatively transactivate the Il9 promoter in T cells. Smad2/3 recruits IRF4 to the Il9 promoter via TGF-β signaling; neither factor alone is sufficient for promoter activation. IRF4 is essential for Smad2/3-mediated Th9 induction. Co-immunoprecipitation, ChIP, luciferase reporter assay, T cell-specific knockout mice Journal of immunology High 23913959
2014 IRF4 is a dominant transcriptional partner of PGC-1α in adipocytes controlling thermogenic gene expression. Cold and cAMP induce IRF4 in adipocytes; IRF4 induces PGC-1α and PRDM16 expression, physically interacts with PGC-1α to drive Ucp1 expression. Knockout of IRF4 in UCP1+ cells reduces thermogenic gene expression, energy expenditure, and causes obesity and cold intolerance. Adipocyte-specific IRF4 knockout and overexpression, co-immunoprecipitation (IRF4–PGC-1α), gene expression profiling, metabolic phenotyping Cell High 24995979
2014 IRF4 interacts with BATF as a cooperating binding partner; both are required for sustained CD8+ T cell effector function following LCMV infection. Absence of IRF4 leads to limited CD8+ T cell responses and chronic viral infection, while protecting from fatal immunopathology. Irf4-/- mice, LCMV infection model, flow cytometry, functional T cell assays Cell death and differentiation High 24531538
2014 IRF4 concentration-dependently controls CD4+ T helper fate: low IRF4 favors Tfh (Bcl6+) fate while high IRF4 promotes Teff (Blimp-1+) fate. Higher IRF4 abundance recruits it to low-affinity binding sites within Teff cis-regulatory elements including those of Prdm1. IRF4 acts as a 'reader' of TCR signal strength to 'write' T helper fate choice. Conditional IRF4 expression system, ChIP-seq, genome-wide occupancy studies, genetic fate-mapping Immunity High 28930660
2014 IRF4 in dendritic cells inhibits IL-12 production and promotes DC migratory behavior, thereby restricting Th1 responses against Leishmania major. Mice with IRF4-deficient DCs showed reduced parasite burden and a Th1-biased immune response with higher IFN-γ production. DC-specific conditional IRF4 knockout mice (CD11c-Cre), Leishmania major infection model, flow cytometry, cytokine measurements Journal of immunology High 24489086
2014 IRF4 is a critical B cell-intrinsic factor required for germinal center formation at an early stage (before GC development), distinct from its role in plasma cell differentiation. Irf4-deficient B cells in chimeric mice failed to participate in GCs in response to protein antigens or infection. Conditional Irf4 deletion in mature B cells, mixed bone marrow chimeric mice, immunization and infection models Journal of immunology High 24591370
2016 IRF4 is required for macrophage alternative (M2) activation downstream of both mTORC2 and IL-4Rα-Stat6 pathways. IRF4 expression requires both mTORC2 and Stat6, and mediates increased glycolysis to support M2 activation. mTORC2 operates in parallel with Stat6 to induce IRF4. mTORC2-deficient macrophages (Rictor knockout), IL-4 stimulation, metabolic assays, gene expression analysis Immunity High 27760338
2016 In multiple myeloma, KDM3A maintains IRF4 expression through H3K9 demethylation of the KLF2 locus; KLF2 in turn directly activates IRF4 transcription, and IRF4 reciprocally upregulates KLF2, forming a positive autoregulatory circuit. Silencing KDM3A, KLF2, or IRF4 reduces MM cell adhesion to bone marrow stromal cells and decreases ITGB7 expression. siRNA knockdown, ChIP, gene expression profiling, adhesion assays, in vivo xenograft Nature communications High 26728187
2017 T cell exhaustion during chronic LCMV infection is driven by high levels of TCR-induced IRF4, BATF, and NFATc1, which promote expression of inhibitory receptors including PD-1 and impair cellular metabolism while repressing TCF1 expression. Reducing IRF4 expression restored functional and metabolic properties of antigen-specific T cells and promoted memory-like T cell development. Transcriptional profiling, chronic vs. acute LCMV infection comparison, genetic reduction of IRF4 Immunity High 29246443
2017 ITK kinase activity controls IRF4 expression downstream of TCR/Ras signaling in Tr1 cell differentiation. ITK-deficient mice lack Tr1 cells, and this defect is rescued by IRF4 expression. Constitutively active HRas rescues IRF4 expression and Tr1 differentiation in Itk-/- cells, placing IRF4 downstream of TCR-ITK-Ras signaling. Itk-/- mice, retroviral rescue (IRF4 and HRas), in vivo parasitic and viral infection models, gene expression analysis Nature communications High 28635957
2017 IRF4 deletion in CD4+ T cells results in progressive CD4+ T cell dysfunction and long-term allograft survival. Mechanistically, IRF4 represses PD-1 and Helios expression; in the absence of IRF4, chromatin accessibility and Helios binding at PD-1 cis-regulatory elements are increased, leading to enhanced PD-1 expression. T cell-specific IRF4 conditional KO, chromatin accessibility (ATAC-seq), ChIP for Helios, allograft transplantation model Immunity High 29221730
2018 In ATLL, IRF4 and BATF3 cooperatively drive ATLL-specific gene expression. HBZ (HTLV-I transcription factor) binds to an ATLL-specific BATF3 super-enhancer, regulating BATF3 and downstream targets including MYC. BET inhibitors collapse this IRF4/BATF3 transcriptional network. RNAi screening, ChIP-seq, xenograft mouse models, BET inhibitor treatment Cancer cell High 30057145
2018 In ATLL, the IRF4 K59R mutation results in higher nuclear expression and greater transcriptional activity than wild-type IRF4. IRF4 is directly bound to genomic regulatory DNA of many transcriptional targets. Overexpression of IRF4 (WT or K59R) in murine bone marrow cells preferentially expands T lymphocytes in vivo. Whole-exome sequencing, ChIP in HTLV-1-transformed cells, retroviral bone marrow transduction/transplantation, nuclear fractionation The Journal of biological chemistry High 29540473
2018 In DLBCL, IRF4 genome-wide occupancy is determined by its cofactors: SPIB provides the dominant IRF4 partner in ABC-DLBCL, and SPIB knockdown depletes IRF4 occupancy genome-wide without acute compensation by PU.1 or BATF. IRF4 adopts either SPIB- or BATF-centric genomic distributions in related post-GC B cell states. ChIP-seq for IRF4, SPIB, PU.1, and BATF; SPIB knockdown; integration with ENCODE data; primary DLBCL cohort analysis Nucleic acids research High 24875472
2018 Ikaros forms heterodimers with IRF4 at zinc finger-IRF composite elements (ZICEs) that embed ISRE motifs. Ikaros/IRF4 binding to ZICEs represses target genes (including Ebf1) during plasma cell differentiation. In contrast, at EICEs, Ikaros/PU.1/IRF4 complexes activate gene expression. Ikaros (but not Aiolos) is essential for IRF4 binding to the ZICE sequence. IRF4 ChIP-seq, co-immunoprecipitation, gene expression analysis, Ikaros knockout in plasma cells Blood advances High 29669755
2019 IRF4 activity in established plasma cells is required for maintaining gene transcription programs specifying plasma cell identity and mitochondrial homeostasis; loss of IRF4 causes apoptosis via pathways that do not directly involve the intrinsic apoptotic pathway regulation. Inducible IRF4 deletion system combined with BCL2 overexpression to separate apoptotic from transcriptional effects; gene expression profiling Cell reports High 31775034
2019 IRAK4 phosphorylates both IRF5 and IRF4 in microglia after ischemia; IRAK4 forms a Myddosome complex with MyD88/IRF5/IRF4, and phosphorylation by IRAK4 causes IRF4 nuclear translocation. IRAK4 inhibition reduces IRF4 phosphorylation and microglial inflammatory responses. Co-immunoprecipitation demonstrating Myddosome complex, Western blot for phosphorylation, IRAK4 inhibitor, OGD model in SIM-A9 cells and primary microglia Cells Medium 33573200
2020 IRF4 controls a core regulatory circuit of CD4+ T cell dysfunction. Mechanistically, IRF4 represses chromatin accessibility at PD-1 cis-regulatory elements and represses Helios binding there. Loss of IRF4 leads to increased PD-1 expression and progressive, eventually irreversible, CD4+ T cell dysfunction. IRF4 conditional KO in T cells, ATAC-seq, ChIP (Helios), PD-L1 blockade reversal experiments Immunity High 29221730
2020 In human intratumoral CD4+ effector Tregs, IRF4 alone or in combination with BATF directly controls a transcriptional program responsible for immunosuppression. Deletion of Irf4 exclusively in Tregs delayed tumor growth in mice. Single-cell transcriptomics, ChIP/ATAC-seq integration, Treg-specific Irf4 conditional KO in tumor models The Journal of clinical investigation High 32125291
2020 In ATL, IRF4 and NF-κB form a coherent feed-forward loop co-occupying super-enhancers and regulatory elements to coordinately regulate T cell function genes including MYC, CCR4, and BIRC3. IRF4-bound regions are preferentially found in super-enhancers over typical enhancers. ChIP-seq for IRF4 and NF-κB, gene expression profiling of primary ATL samples, genetic inhibition of BIRC3 Blood High 31972002
2020 TCR signal strength is transduced by ITK kinase activity to control the kinetics of Irf4 mRNA induction in CD8+ T cells; weaker TCR signals cause delayed Irf4 transcription onset and reduced total IRF4 protein, creating heterogeneity in clonal CD8+ T cell expansion. NFAT1 activation kinetics are unaffected, implicating a distinct IRF4-controlling pathway. Single-cell live imaging, NFAT1 reporter, Irf4 mRNA kinetics measurement, ITK-deficient cells, antigen potency titration Journal of immunology High 32493815
2021 BATF and IRF4 cooperate to counter T cell exhaustion in tumor-infiltrating CAR T cells. BATF overexpression in CAR T cells decreased exhaustion markers, increased effector cytokines, and required BATF-IRF4 interaction: a BATF variant unable to interact with IRF4 failed to rescue T cell survival and antitumor function. CAR T cell tumor mouse models, BATF overexpression, BATF mutant unable to bind IRF4, flow cytometry, memory T cell tracking Nature immunology High 34282330
2021 The crystal structure of the IRF4/ISRE homodimeric complex reveals that homodimer formation is mediated exclusively through protein-DNA contacts with substantial DNA deformation, and not by protein-protein contacts. This contrasts with the IRF4 heterodimeric form where DNA-bound IRF4 physically interacts with PU.1. Hotspot residues Arg98, Cys99, and Asn102 contact both consensus and non-consensus sequences with a flexible L1 loop. IRF4-L116R (CLL-associated mutant) binds more robustly to DNA, explaining gain of function. X-ray crystallography of IRF4/ISRE homodimeric complex, mutagenesis, comparison with heterodimeric complex structure Nucleic acids research High 33533913
2021 RNF2 E3 ubiquitin ligase interacts with IRF4 and promotes its ubiquitination and proteasomal degradation in colon cancer cells, reducing IRF4 protein levels and promoting tumor proliferation and invasion. Co-immunoprecipitation (RNF2-IRF4 interaction), ubiquitination assay, RNF2 overexpression/knockdown with rescue by IRF4, xenograft mouse model Biochimica et biophysica acta. Molecular cell research Medium 34670117
2021 KLF2 directly transcriptionally activates IRF4 expression by binding to the IRF4 promoter (demonstrated by ChIP and luciferase assay). IRF4 in turn promotes HDAC7 expression by binding to the HDAC7 promoter, forming a KLF2-IRF4-HDAC7 axis that protects against neuronal apoptosis in hypoxic-ischemic brain damage. Dual luciferase reporter assay, ChIP, KLF2 overexpression, HIBD rat model Cell death discovery Medium 35091544
2021 SOX10 directly induces IRF4 expression in melanoma cells, and IRF4 in turn represses IRF1 transcription, thereby suppressing PD-L1 expression and immunogenicity independently of the JAK-STAT pathway. Pharmacological suppression of SOX10 increases IRF1 and PD-L1 expression. Genetic knockout/knockdown of SOX10 and IRF4, pharmacological inhibition, PD-L1 reporter assays, in vivo anti-PD-1 combination model Cancer research High 34728538
2022 IFNβ suppresses the JMJD3-IRF4-dependent pathway in macrophages by lowering the α-ketoglutarate/succinate ratio, which inhibits JMJD3 (histone demethylase) activity and consequently reduces IRF4 expression and M2 polarization. Supplementation with α-ketoglutarate reverses IFNβ-mediated suppression of IRF4 and M2 activation. Metabolomics, isotope tracing, Jmjd3 inhibition, α-ketoglutarate supplementation, macrophage polarization assays in GM-CSF and IL-4-stimulated macrophages Cell reports High 35443173
2023 A heterozygous IRF4 p.T95R mutation in the DNA-binding domain causes autosomal dominant combined immunodeficiency (CID). IRF4-T95R simultaneously acts as a hypermorph (higher DNA-binding affinity), hypomorph (reduced canonical transcriptional activity), and neomorph (binding to non-canonical DNA sites and activating novel gene sets). This multimorphic behavior disrupts normal lymphocyte biology. Patient genetics, knock-in mouse model, in vitro DNA binding assays, transcriptome profiling of patient cells, motif analysis Science immunology High 36662884
2023 IRF4 in skeletal muscle transcriptionally regulates FSTL1 (follistatin-like protein 1) expression, which is secreted and acts on the liver to promote hepatic steatosis and inflammation in NASH. Skeletal muscle-specific IRF4 KO ameliorates liver pathology without affecting body weight; inducing FSTL1 in F4MKO muscles restores liver pathology. Skeletal muscle-specific IRF4 KO mice, NASH diet model, dual luciferase assay (IRF4→FSTL1 promoter), proteomics, co-culture experiments Nature communications High 37770480
2023 IRF4 integrates signals during NK cell responses to mouse cytomegalovirus infection, acting as a secondary metabolic checkpoint controlling nutrient uptake required for NK cell survival, expansion, and memory generation. Loss of IRF4 impaired expansion and differentiation of virus-specific NK cells. NK cell-specific IRF4 KO, MCMV infection model, metabolic profiling, antigen-specific NK cell tracking Nature immunology High 37697097
2023 The recurrent somatic IRF4-C99R mutation (found in classic Hodgkin lymphoma) fundamentally alters IRF4 DNA-binding: it causes loss of binding to canonical IRF motifs and neomorphic gain of binding to canonical and non-canonical AICE composite elements, blocking plasma cell induction and upregulating disease-specific genes via non-canonical AP-1-IRF composite elements. Structural and binding studies of IRF4-C99R, ChIP-seq comparison of WT vs. C99R IRF4, plasma cell differentiation assay, gene expression profiling Nature communications High 37935654
2024 ARID1A (SWI/SNF chromatin remodeling complex) is required for IRF4 expression and physically associates with IRF4 protein on chromatin in multiple myeloma. Deleting Arid1a in activated murine B cells disrupts IRF4-dependent transcriptional networks and blocks plasma cell differentiation. Targeting SWI/SNF leads to rapid loss of IRF4-target gene expression and MYC-amplified oncogenic expression. Functional genomics screening, spatial proteomics, chromatin mapping (ChIP-seq/ATAC-seq), Arid1a conditional KO in B cells, SMARCA2/4 inhibitors in MM cell lines Cancer cell High 38906156
2024 METTL3 promotes IRF4 expression in an m6A-dependent manner in B cells/plasma cells of SLE patients, driving plasma cell infiltration-mediated kidney damage. IRF4 knockdown partially reduces METTL3-induced kidney injury; downstream IRF4 targets Cxcl1, Bcl3, and Fos regulate TNF signaling. MeRIP-seq (m6A profiling), MeRIP-qPCR of IRF4 transcripts, AAV-mediated METTL3 overexpression and IRF4 knockdown in MRL/lpr mice, flow cytometry BMC medicine Medium 39501302
2020 IRF4 regulates skeletal muscle glycogen content and exercise capacity by controlling expression of PTG (protein targeting to glycogen). Muscle-specific IRF4 KO increases glycogen content and exercise capacity; IRF4 overexpression decreases them. Knockdown of PTG reverses the effects of IRF4 absence in vivo. Skeletal muscle-specific IRF4 KO and OE mice, exercise capacity testing, glycogen measurement, PTG knockdown rescue experiment Advanced science High 33042761

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination. Nature immunology 630 16767092
2016 Metabolic Reprogramming Mediated by the mTORC2-IRF4 Signaling Axis Is Essential for Macrophage Alternative Activation. Immunity 512 27760338
2017 Transcription Factor IRF4 Promotes CD8+ T Cell Exhaustion and Limits the Development of Memory-like T Cells during Chronic Infection. Immunity 396 29246443
1997 Deregulation of MUM1/IRF4 by chromosomal translocation in multiple myeloma. Nature genetics 290 9326949
2021 BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells. Nature immunology 286 34282330
2014 IRF4 is a key thermogenic transcriptional partner of PGC-1α. Cell 263 24995979
1995 Molecular cloning of LSIRF, a lymphoid-specific member of the interferon regulatory factor family that binds the interferon-stimulated response element (ISRE). Nucleic acids research 213 7541907
1996 A novel interferon regulatory factor family transcription factor, ICSAT/Pip/LSIRF, that negatively regulates the activity of interferon-regulated genes. Molecular and cellular biology 182 8657101
2014 IRF4 at the crossroads of effector T-cell fate decision. European journal of immunology 179 24782159
2019 Microglial IRF5-IRF4 regulatory axis regulates neuroinflammation after cerebral ischemia and impacts stroke outcomes. Proceedings of the National Academy of Sciences of the United States of America 147 31892541
2020 IRF4 instructs effector Treg differentiation and immune suppression in human cancer. The Journal of clinical investigation 145 32125291
2012 The diverse roles of IRF4 in late germinal center B-cell differentiation. Immunological reviews 117 22500833
2018 Targeting the HTLV-I-Regulated BATF3/IRF4 Transcriptional Network in Adult T Cell Leukemia/Lymphoma. Cancer cell 109 30057145
2017 The IRF4 Gene Regulatory Module Functions as a Read-Write Integrator to Dynamically Coordinate T Helper Cell Fate. Immunity 109 28930660
2016 Essential role of interferon regulatory factor 4 (IRF4) in immune cell development. Archives of pharmacal research 100 27826752
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2014 Transcription factor IRF4 regulates germinal center cell formation through a B cell-intrinsic mechanism. Journal of immunology (Baltimore, Md. : 1950) 96 24591370
2009 IRF4 gene rearrangements define a subgroup of CD30-positive cutaneous T-cell lymphoma: a study of 54 cases. The Journal of investigative dermatology 96 19812605
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2013 Smad2/3 and IRF4 play a cooperative role in IL-9-producing T cell induction. Journal of immunology (Baltimore, Md. : 1950) 95 23913959
2016 The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival. Nature communications 91 26728187
2017 Ablation of Transcription Factor IRF4 Promotes Transplant Acceptance by Driving Allogenic CD4+ T Cell Dysfunction. Immunity 82 29221730
2002 Expression pattern of MUM1/IRF4 in the spectrum of pathology of Hodgkin's disease. British journal of haematology 74 11972519
2014 IRF4 and BATF are critical for CD8⁺ T-cell function following infection with LCMV. Cell death and differentiation 68 24531538
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2010 Regulation of chromatin architecture by the PWWP domain-containing DNA damage-responsive factor EXPAND1/MUM1. Molecular cell 63 20347427
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2011 The Arabidopsis transcription factor LUH/MUM1 is required for extrusion of seed coat mucilage. Plant physiology 61 21518777
2015 Indolent lymphomas in the pediatric population: follicular lymphoma, IRF4/MUM1+ lymphoma, nodal marginal zone lymphoma and chronic lymphocytic leukemia. Virchows Archiv : an international journal of pathology 60 26416032
2010 Molecular cloning and characterization of interferon regulatory factors 4 and 8 (IRF-4 and IRF-8) in rainbow trout, Oncorhynchus mykiss. Fish & shellfish immunology 60 20298789
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2021 Selective antisense oligonucleotide inhibition of human IRF4 prevents malignant myeloma regeneration via cell cycle disruption. Cell stem cell 51 33476575
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2020 Suppression of Inflammasome Activation by IRF8 and IRF4 in cDCs Is Critical for T Cell Priming. Cell reports 50 32375053
2014 Dual mechanisms by which miR-125b represses IRF4 to induce myeloid and B-cell leukemias. Blood 50 25006123
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2014 IRF4 in dendritic cells inhibits IL-12 production and controls Th1 immune responses against Leishmania major. Journal of immunology (Baltimore, Md. : 1950) 48 24489086
2014 SPIB and BATF provide alternate determinants of IRF4 occupancy in diffuse large B-cell lymphoma linked to disease heterogeneity. Nucleic acids research 44 24875472
2021 The IKZF1-IRF4/IRF5 Axis Controls Polarization of Myeloma-Associated Macrophages. Cancer immunology research 43 33563611
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2023 A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency. Science immunology 35 36662884
2017 Fra-2 regulates B cell development by enhancing IRF4 and Foxo1 transcription. The Journal of experimental medicine 35 28566276
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1998 Cooperative interaction between the DNA-binding domains of PU.1 and IRF4. Journal of molecular biology 34 9642085
2020 Inhibition of IRF4 in dendritic cells by PRR-independent and -dependent signals inhibit Th2 and promote Th17 responses. eLife 33 32014112
2018 DOT1L inhibition blocks multiple myeloma cell proliferation by suppressing IRF4-MYC signaling. Haematologica 33 30171029
2017 Hypoxia-inducible microRNA-210 regulates the DIMT1-IRF4 oncogenic axis in multiple myeloma. Cancer science 33 28164410
2020 Feed-forward regulatory loop driven by IRF4 and NF-κB in adult T-cell leukemia/lymphoma. Blood 32 31972002
2010 Cooperation between deficiencies of IRF-4 and IRF-8 promotes both myeloid and lymphoid tumorigenesis. Blood 32 20585039
2019 Ikzf1 regulates embryonic T lymphopoiesis via Ccr9 and Irf4 in zebrafish. The Journal of biological chemistry 31 31511326
2023 Metabolic crosstalk between skeletal muscle cells and liver through IRF4-FSTL1 in nonalcoholic steatohepatitis. Nature communications 30 37770480
2019 IRF4-dependent dendritic cells regulate CD8+ T-cell differentiation and memory responses in influenza infection. Mucosal immunology 29 31089186
2015 Irf4 Regulates the Choice between T Lymphoid-Primed Progenitor and Myeloid Lineage Fates during Embryogenesis. Developmental cell 29 26300447
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2023 Control of nutrient uptake by IRF4 orchestrates innate immune memory. Nature immunology 27 37697097
2023 Regulatory effects of IRF4 on immune cells in the tumor microenvironment. Frontiers in immunology 26 36814912
2022 The dynamic functions of IRF4 in B cell malignancies. Clinical and experimental medicine 26 36495369
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2015 MMSET regulates expression of IRF4 in t(4;14) myeloma and its silencing potentiates the effect of bortezomib. Leukemia 26 26196464
2008 The expression of MUM1 in cutaneous T-cell lymphoproliferative disorders. Human pathology 26 18234282
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2022 Jmjd3/IRF4 axis aggravates myeloid fibroblast activation and m2 macrophage to myofibroblast transition in renal fibrosis. Frontiers in immunology 24 36159833
2021 IRF-4 deficiency reduces inflammation and kidney fibrosis after folic acid-induced acute kidney injury. International immunopharmacology 24 34555644
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2021 Phosphorylation of Microglial IRF5 and IRF4 by IRAK4 Regulates Inflammatory Responses to Ischemia. Cells 23 33573200
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2020 Activation of the Tec Kinase ITK Controls Graded IRF4 Expression in Response to Variations in TCR Signal Strength. Journal of immunology (Baltimore, Md. : 1950) 23 32493815
2018 An activating mutation of interferon regulatory factor 4 (IRF4) in adult T-cell leukemia. The Journal of biological chemistry 23 29540473
2020 IRF4 in Skeletal Muscle Regulates Exercise Capacity via PTG/Glycogen Pathway. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 22 33042761
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2024 METTL3 facilitates kidney injury through promoting IRF4-mediated plasma cell infiltration via an m6A-dependent manner in systemic lupus erythematosus. BMC medicine 21 39501302
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2009 IRF4 is modulated by CD40L and by apoptotic and anti-proliferative signals in Hodgkin lymphoma. British journal of haematology 17 19821826
2018 Immunohistochemical Labeling of Multiple Myeloma Oncogene 1/Interferon Regulatory Factor 4 (MUM1/IRF-4) in Canine Cutaneous Histiocytoma. Veterinary pathology 16 29444632
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2015 IRF4-Dependent and IRF4-Independent Pathways Contribute to DC Dysfunction in Lupus. PloS one 14 26544714