Suppression of FOXP3 expression by the AP-1 family transcription factor BATF3 requires partnering with IRF4

Arnold, Preston R.; Wen, Mou; Zhang, Lei; Ying, Yuanlin; Xiao, Xiang; Chu, Xiufeng; Wang, Guangchuan; Zhang, Xiaolong; Mao, Zhuyun; Zhang, Aijun; Hamilton, Dale J.; Chen, Wenhao; Li, Xian Chang

doi:10.3389/fimmu.2022.966364

Cited by 9 publications

(11 citation statements)

References 44 publications

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“…Previous studies have shown that metabolic pathways are 'rewired' upon activation and differentiation of resting lymphocytes shifting from oxidative phosphorylation to aerobic glycolysis fulfilling the bioenergetic demands during proliferation, differentiation and the biosynthesis of precursors 19 . IRF4-driven metabolic switch towards glycolysis has been demonstrated before for CD8 + T 20 and Treg cells 9 , which is in line with our data. Distinct metabolic programs have also been associated with the polarization along the Th17 cell and Treg cell axis and oxidative phosphorylation has been correlated with a Treg cell phenotype 21 .…”

Section: Irf4 Transcriptionally Regulates Distinct Effector Functions...supporting

confidence: 93%

“…In Treg cells, IRF4, in concert with BATF3, regulates the expression of the lineage-specific TF FOXP3 and hence controls (i)Treg induction 9 . Despite its repressive function on FOXP3 expression, IRF4 acts as a downstream target of FOXP3 and is required for the development of fully functional Treg cells and their immunomodulatory activity in a cellular context 6,9 . In a complex, IRF4 and FOXP3 control the expression of gene loci 5 associated with Treg cell suppressive properties, e.g., Il10 and Icos 10,11 .…”

Section: Introductionmentioning

confidence: 99%

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Unveiling IRF4-steered regulation of context-dependent effector programs in Th17 and Treg cells

Gabele,

Sprang,

Cihan

et al. 2023

Preprint

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The transcription factor interferon regulatory factor 4 (IRF4) is crucial for the differentiation and fate determination of pro-inflammatory T helper (Th)17 and the functionally opposing group of immunomodulatory regulatory T (Treg) cells. However, molecular mechanisms of how IRF4 steers diverse transcriptional programs in Th17 and Treg cells are far from being definitive. To unveil IRF4-driven lineage determination in Th17 and Treg cells, we integrated data derived from affinity-purification and full mass spectrometry-based proteome analysis with chromatin immune precipitation sequencing (ChIP-Seq). This allowed the characterization of subtype-specific molecular programs and the identification of novel, previously unknown IRF4 interactors in the Th17/Treg context, such as RORγt, AHR, IRF8, BACH2, SATB1, and FLI1. Moreover, our data reveal that most of these transcription factors are recruited to IRF composite elements for the regulation of cell type-specific transcriptional programs providing a valuable resource for studying IRF4-mediated gene regulatory programs in pro- and anti-inflammatory immune responses.

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Section: Irf4 Transcriptionally Regulates Distinct Effector Functions...supporting

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Unveiling IRF4-steered regulation of context-dependent effector programs in Th17 and Treg cells

Gabele,

Sprang,

Cihan

et al. 2023

Preprint

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“…Recently, Arnold PR. et al demonstrate that BATF3, a TF of AP-1 family, partnering with IRF4 to repress FOXP3, and so Treg production (40). On the opposite, both IRF4 and BRDM1 are correlated with CTLA4, a Treg marker, and with SOCS3, a regulator of STAT3 and downregulated in CCC.…”

Section: Discussionmentioning

confidence: 99%

Exploring global and specific pathogenic mechanisms in Chronic Chagas Cardiomyopathy through multi-omics integration

Brochet,

Kalil,

Procaccio

et al. 2023

Preprint

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Chagas disease is a neglected disease from South America caused by a parasite, Trypanosoma cruzi. While most of infected people remains asymptomatic, around 30% develop Chronic Chagas Cardiomyopathy (CCC), a very lethal cardiomyopathy characterized by an exacerbate inflammatory response. The last few years, our team has set up multiple omics analysis. Briefly, we have pointed the over-expression of many genes involved in the Th1 lymphocyte response, as well as some epigenetic features potentially involved in their regulation, including miRNA, lncRNA and methylation site. Moreover, some mitochondria mutation seems to predispose to the development of CCC. In order to understand and characterize the impact of genetic and epigenetic elements on the pathogenic process associated to CCC, we have performed here a multi-omics integration, combining transcriptomic, methylomic, miRNomic and mitochondria sequencing. We have identified two distinct pathogenic pathways that vary among patients with chronic Chagas cardiomyopathy (CCC). One pathway is primarily influenced by IRF4, a transcription factor known for its involvement in the development of both B and T cells, while the other is driven by TLR signaling. Notably, genes related to B cells play a role in both of these processes. Additionally, we have detected certain similarities in the B cell receptors of all CCC patients, which may potentially contribute to autoimmunity. While further analysis is necessary to validate these findings, they collectively enhance our understanding of the pathogenic mechanisms associated with CCC.

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“…Foxp3 is a lineage-defining TF for Tregs and the key regulator of its development and function ( 52 , 53 ). IRF4, which acts downstream of Foxp3, can physically and functionally interact with Foxp3 and cooperate with BATF3 to regulate Foxp3 expression ( 54 , 55 ), which instructs effector Treg cell differentiation and immune suppression ( 56 ). Moreover, Blimp1 is a target of Foxp3 in Treg cells, and it is directly induced by IRF4 ( 57 , 58 ).…”

Section: Roles Of Irf4 In the Differentiation And Function Of Cd4+ T ...mentioning

confidence: 99%

Regulatory effects of IRF4 on immune cells in the tumor microenvironment

Liang²,

Li³

et al. 2023

Front. Immunol.

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The tumor microenvironment (TME) is implicated in tumorigenesis, chemoresistance, immunotherapy failure and tumor recurrence. Multiple immunosuppressive cells and soluble secreted cytokines together drive and accelerate TME disorders, T cell immunodeficiency and tumor growth. Thus, it is essential to comprehensively understand the TME status, immune cells involved and key transcriptional factors, and extend this knowledge to therapies that target dysfunctional T cells in the TME. Interferon regulatory factor 4 (IRF4) is a unique IRF family member that is not regulated by interferons, instead, is mainly induced upon T-cell receptor signaling, Toll-like receptors and tumor necrosis factor receptors. IRF4 is largely restricted to immune cells and plays critical roles in the differentiation and function of effector cells and immunosuppressive cells, particularly during clonal expansion and the effector function of T cells. However, in a specific biological context, it is also involved in the transcriptional process of T cell exhaustion with its binding partners. Given the multiple effects of IRF4 on immune cells, especially T cells, manipulating IRF4 may be an important therapeutic target for reversing T cell exhaustion and TME disorders, thus promoting anti-tumor immunity. This study reviews the regulatory effects of IRF4 on various immune cells in the TME, and reveals its potential mechanisms, providing a novel direction for clinical immune intervention.

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Suppression of FOXP3 expression by the AP-1 family transcription factor BATF3 requires partnering with IRF4

Cited by 9 publications

References 44 publications

Unveiling IRF4-steered regulation of context-dependent effector programs in Th17 and Treg cells

Unveiling IRF4-steered regulation of context-dependent effector programs in Th17 and Treg cells

Exploring global and specific pathogenic mechanisms in Chronic Chagas Cardiomyopathy through multi-omics integration

Regulatory effects of IRF4 on immune cells in the tumor microenvironment

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