Prostaglandin E2 Suppresses Antifungal Immunity by Inhibiting Interferon Regulatory Factor 4 Function and Interleukin-17 Expression in T Cells

Abstract Background: Interferon regulatory factor 4 (IRF4) is a transcription factor that involves in immune cells differentiation. However, it is not clear the relationship between IRF4 and tumor prognosis and immune infiltration.Methods: IRF4 expression levels in different cancers and corresponding normal tissues were analyzed by Oncomine database and Tumor Immune Estimation Resource (TIMER). The prognosis value of IRF4 was assessed by PrognoScan and Kaplan-Meier plotter. The correlation between IRF4 and tumor-infiltrating immune cells and immune cells markers was performed by TIMER and Gene Expression Profiling Interactive Analysis (GEPIA). In addition, we explored the genes regulated by IRF4 in Gene Transcription Regulation Database (GTRD) and then put the above genes in Enrich online tool for Gene Ontology (GO) and pathway enrichment analysis.Results: Decreased expression levels of IRF4 were observed in breast and colorectal cancers. Survival analysis shown that high level of IRF4 was associated with better prognostic outcome in breast and colorectal cancer patients. IRF4 expression was positively correlated with infiltrating levels of B cells, CD8+ T cells, T cells (general), dendritic cells (DCs), Th1, T cell exhaustion and monocytes, and immune cells markers. Beside, functional enrichment analysis of the potential genes regulated by IRF4 indicated that IRF4 may be involved in many important biological processes including immune regulation by regulating various genes.Conclusions: High expression of IRF4 shown better prognostic outcome for breast and colorectal cancers. IRF4 was associated with immune infiltration in breast and colorectal cancers. Therefore, IRF4 maybe serve as a potential prognostic biomarker in breast and colorectal cancers with immune infiltration.

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Modulation of T Cell Cytokine Production by Interferon Regulatory Factor-4

Journal of Biological Chemistry ◽

10.1074/jbc.m205895200 ◽

2002 ◽

Vol 277 (51) ◽

pp. 49238-49246 ◽

Cited By ~ 76

Author(s):

Chuan-Min Hu ◽

So Young Jang ◽

Jessica C. Fanzo ◽

Alessandra B. Pernis

Keyword(s):

T Cells ◽

T Cell ◽

Molecular Mechanisms ◽

Cytokine Production ◽

Interferon Regulatory Factor ◽

Luciferase Reporter ◽

Regulatory Factor ◽

A Site ◽

Interferon Regulatory Factor 4 ◽

Cell Cytokine Production

Production of cytokines is one of the major mechanisms employed by CD4+T cells to coordinate immune responses. Although the molecular mechanisms controlling T cell cytokine production have been extensively studied, the factors that endow T cells with their ability to produce unique sets of cytokines have not been fully characterized. Interferon regulatory factor (IRF)-4 is a lymphoid-restricted member of the interferon regulatory factor family of transcriptional regulators, whose deficiency leads to a profound impairment in the ability of mature CD4+T cells to produce cytokines. In these studies, we have investigated the mechanisms employed by IRF-4 to control cytokine synthesis. We demonstrate that stable expression of IRF-4 in Jurkat T cells not only leads to a strong enhancement in the synthesis of interleukin (IL)-2, but also enables these cells to start producing considerable amounts of IL-4, IL-10, and IL-13. Transient transfection assays indicate that IRF-4 can transactivate luciferase reporter constructs driven by either the human IL-2 or the human IL-4 promoter. A detailed analysis of the effects of IRF-4 on the IL-4 promoter reveals that IRF-4 binds to a site adjacent to a functionally important NFAT binding element and that IRF-4 cooperates with NFATc1. These studies thus support the notion that IRF-4 represents one of the lymphoid-specific components that control the ability of T lymphocytes to produce a distinctive array of cytokines.

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Interferon regulatory factor 4 deficiency in CD8 + T cells abrogates terminal effector differentiation and promotes transplant acceptance

Immunology ◽

10.1111/imm.13258 ◽

2020 ◽

Vol 161 (4) ◽

pp. 364-379

Author(s):

Dawei Zou ◽

Jinfei Fu ◽

Zhiyong Guo ◽

Wenhao Chen

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Interferon Regulatory Factor ◽

Regulatory Factor ◽

Interferon Regulatory Factor 4 ◽

Terminal Effector

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Th17 Cell-Mediated Colitis Is Positively Regulated by Interferon Regulatory Factor 4 in a T Cell-Extrinsic Manner

Frontiers in Immunology ◽

10.3389/fimmu.2020.590893 ◽

2021 ◽

Vol 11 ◽

Author(s):

Vera Buchele ◽

Patrick Konein ◽

Tina Vogler ◽

Timo Kunert ◽

Karin Enderle ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Th17 Cell ◽

Interferon Regulatory Factor ◽

T Cell Subsets ◽

Regulatory Factor ◽

Th17 Response ◽

Immune Mediated ◽

Interferon Regulatory Factor 4

Inflammatory bowel diseases (IBDs) are characterized by chronic, inflammatory gastrointestinal lesions and often require life-long treatment with immunosuppressants and repetitive surgical interventions. Despite progress in respect to the characterization of molecular mechanisms e.g. exerted by TNF-alpha, currently clinically approved therapeutics fail to provide long-term disease control for most patients. The transcription factor interferon regulatory factor 4 (IRF4) has been shown to play important developmental as well as functional roles within multiple immune cells. In the context of colitis, a T cell-intrinsic role of IRF4 in driving immune-mediated gut pathology is established. Here, we conversely addressed the impact of IRF4 inactivation in non-T cells on T cell driven colitis in vivo. Employing the CD4+CD25− naïve T cell transfer model, we found that T cells fail to elicit colitis in IRF4-deficient compared to IRF4-proficient Rag1−/− mice. Reduced colitis activity in the absence of IRF4 was accompanied by hampered T cell expansion both within the mesenteric lymph node (MLN) and colonic lamina propria (cLP). Furthermore, the influx of various myeloids, presumably inflammation-promoting cells was abrogated overall leading to a less disrupted intestinal barrier. Mechanistically, gene profiling experiments revealed a Th17 response dominated molecular expression signature in colon tissues of IRF4-proficient, colitic Rag1−/− but not in colitis-protected Rag1−/−Irf4−/− mice. Colitis mitigation in Rag1−/−Irf4−/− T cell recipients resulted in reduced frequencies and absolute numbers of IL-17a-producing T cell subsets in MLN and cLP possibly due to a regulation of conventional dendritic cell subset 2 (cDC2) known to impact Th17 differentiation. Together, extending the T cell-intrinsic role for IRF4 in the context of Th17 cell driven colitis, the provided data demonstrate a Th17-inducing and thereby colitis-promoting role of IRF4 through a T cell-extrinsic mechanism highlighting IRF4 as a putative molecular master switch among transcriptional regulators driving immune-mediated intestinal inflammation through both T cell-intrinsic and T cell-extrinsic mechanisms. Future studies need to further dissect IRF4 controlled pathways within distinct IRF4-expressing myeloid cell types, especially cDC2s, to elucidate the precise mechanisms accounting for hampered Th17 formation and, according to our data, the predominant mechanism of colitis protection in Rag1−/−Irf4−/− T cell receiving mice.

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Expression of Interferon Regulatory Factor 4 in Chronic Myeloid Leukemia: Correlation With Response to Interferon Alfa Therapy

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.19.3331 ◽

2000 ◽

Vol 18 (19) ◽

pp. 3331-3338 ◽

Cited By ~ 31

Author(s):

Manuel Schmidt ◽

Andreas Hochhaus ◽

Sven A. König-Merediz ◽

Cornelia Brendel ◽

Jutta Proba ◽

...

Keyword(s):

T Cells ◽

Chronic Myeloid Leukemia ◽

Healthy Volunteers ◽

Myeloid Leukemia ◽

Lymphoblastic Leukemia ◽

Cytogenetic Response ◽

Interferon Regulatory Factor ◽

Interferon Alfa ◽

Regulatory Factor ◽

Interferon Regulatory Factor 4

PURPOSE: Mice experiments have established an important role for interferon regulatory factor (IRF) family members in hematopoiesis. We wanted to study the expression of interferon regulatory factor 4 (IRF4) in various hematologic disorders, especially chronic myeloid leukemia (CML), and its association with response to interferon alfa (IFN-α) treatment in CML. MATERIALS AND METHODS: Blood samples from various hematopoietic cell lines, different leukemia patients (70 CML, 29 acute myeloid leukemia [AML], 10 chronic myelomonocytic leukemia [CMMoL], 10 acute lymphoblastic leukemia, and 10 chronic lymphoid leukemia patients), and 33 healthy volunteers were monitored for IRF4 expression by reverse transcriptase polymerase chain reaction. Then, with a focus on CML, the IRF4 level was determined in sorted cell subpopulations from CML patients and healthy volunteers and in in vitro–stimulated CML cells. Furthermore, IRF4 expression was compared in the CML samples taken before IFN-α therapy and in 47 additional CML samples taken during IFN-α therapy. IRF4 expression was then correlated with cytogenetic response to IFN-α. RESULTS: IRF4 expression was significantly impaired in CML, AML, and CMMoL samples. The downregulation of IRF4 in CML samples was predominantly found in T cells. In CML patients during IFN-α therapy, a significant increase in IRF4 levels was detected, and this was also observed in sorted T cells from CML patients. The increase seen during IFN-α therapy was not due to different blood counts. In regard to the cytogenetic response with IFN-α, a good response was associated with high IRF4 expression. CONCLUSION: IRF4 expression is downregulated in T cells of CML patients, and its increase is associated with a good response to IFN-α therapy. These data suggest IRF4 expression as a useful marker to monitor, if not predict, response to IFN-α in CML.

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The transcription factor Interferon Regulatory Factor 4 is required for the generation of protective effector CD8+ T cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1309378110 ◽

2013 ◽

Vol 110 (37) ◽

pp. 15019-15024 ◽

Cited By ~ 53

Author(s):

F. Raczkowski ◽

J. Ritter ◽

K. Heesch ◽

V. Schumacher ◽

A. Guralnik ◽

...

Keyword(s):

T Cells ◽

Transcription Factor ◽

Cd8 T Cells ◽

Interferon Regulatory Factor ◽

Regulatory Factor ◽

Interferon Regulatory Factor 4

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Interferon regulatory factor 4 differentially regulates the production of Th2 cytokines in naive vs. effector/memory CD4+ T cells

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0803171105 ◽

2008 ◽

Vol 105 (41) ◽

pp. 15890-15895 ◽

Cited By ~ 32

Author(s):

K. Honma ◽

D. Kimura ◽

N. Tominaga ◽

M. Miyakoda ◽

T. Matsuyama ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Interferon Regulatory Factor ◽

Effector Memory ◽

Th2 Cytokines ◽

Regulatory Factor ◽

Interferon Regulatory Factor 4 ◽

Memory Cd4 T Cells

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Interferon Regulatory Factor 4 Correlated With Immune Cells Infiltration Could Predict Prognosis for Patients With Lung Adenocarcinoma

Frontiers in Oncology ◽

10.3389/fonc.2021.698465 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xuanzong Li ◽

Shujun Zhai ◽

Jianbo Zhang ◽

Dai Zhang ◽

Shijiang Wang ◽

...

Keyword(s):

T Cells ◽

Lung Adenocarcinoma ◽

Signaling Pathway ◽

Cell Receptor ◽

Interferon Regulatory Factor ◽

Regulatory Factor ◽

Receptor Signaling Pathway ◽

Interferon Regulatory Factor 4 ◽

Cell Receptor Signaling

BackgroundImmune related interferon regulatory factor 4 (IRF4) is a member of the IRF family, whereas the clinical significance and possible role of IRF4 in lung adenocarcinoma (LUAD) remains unclear. We aimed to investigate the role of IRF4 in predicting the prognosis of LUAD patients.MethodsUsing The Cancer Genome Atlas (TCGA) database and our immunohistochemical (IHC) cohort, we analyzed the correlation between IRF4 expression and clinical characteristics, and the prognostic value of IRF4 was also evaluated in LUAD. The potential biological functions of IRF4 in LUAD were analyzed by Gene Set Enrichment Analysis (GSEA). The relationship between IRF4 and immune cell infiltration were evaluated by TISIDB database and our own IHC cohort. In addition, an immune checkpoint inhibitor (ICI) treated cohort from Gene Expression Omnibus database was used to determine the role of IRF4 in LUAD patients with immunotherapy.ResultsWe found that either mRNA or protein expression level of IRF4 was significantly higher in LUAD than in normal tissues (P < 0.001). The elevate in IRF4 expression in LUAD was significantly associated with the earlier clinical stage (P = 0.002). Patients with LUAD and IRF4 high expression correlated with significant longer overall survival in both TCGA database (P < 0.05) and our IHC-cohort (P = 0.001). Our results also demonstrated that IRF4 could serve as an independent favorable prognostic factor in patients with LUAD. GSEA analysis indicated that high IRF4 expression group enriched with several immune-related pathways, such as B cell receptor signaling pathway, T cell receptor signaling pathway and cytokine-cytokine receptor interaction signaling pathway. In LUAD, IRF4 positively correlated with several different immune infiltrations including various B cells, CD8+ T cells and CD4+ T cells both in mRNA and protein levels. Additionally, we found that the expression of IRF4 was positively associated with PD-1 and PD-L1 mRNA expression levels, and IRF4 high expression predicted moderate better survival in LUAD with immunotherapy (P = 0.071).ConclusionsOur results suggested that IRF4 was associated with higher B cells and T cells infiltration levels and might be a favorable prognostic biomarker in LUAD patients, whereas the potential prognostic role of IRF4 in ICI-treated patients needed further exploration.

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