BATF3-dependent IRF4 binding inhibits FOXP3 in differentiating Tregs
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE211182 | GEO | 2022/08/16
REPOSITORIES: GEO
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Project description:Cross-presentation of cell-associated antigens is carried out by classical DCs (cDCs) and monocyte-derived DCs (Mo-DCs), but whether a similar or distinct program exists for this process is unknown. In examining this issue, we discovered that only Ly-6ChiTremL4– monocytes, but not Ly-6ChiTremL4+ monocytes, can differentiate into Zbtb46+ Mo-DCs in response to GM-CSF and IL-4. However, Ly-6ChiTremL4+ monocytes were committed to Nur77-dependent development of Ly-6CloTremL4+ monocytes. Further, differentiation of monocytes with GM-CSF required addition of IL-4 to generate Zbtb46+ Mo-DCs that cross-presented as efficiently as CD24+ cDCs, which was accompanied by increased Batf3 and Irf4 expression. Unlike cDCs, Mo-DCs required only IRF4, and not Batf3, for cross-presentation. Further, Irf4–/– monocytes failed to develop into Zbtb46+ Mo-DCs, and instead developed into macrophages. Thus, cDCs and Mo-DCs use distinct transcriptional programs for cross-presentation that may drive different antigen-processing pathways. These differences may influence development of therapeutic DC vaccines based on Mo-DCs.
2016-05-25 | GSE75014 | GEO
Project description:Interferon regulatory factor 4 (IRF4) is an IRF family transcription factor with critical roles in lymphoid development and in regulating the immune response. IRF4 binds DNA weakly owing to a carboxy-terminal auto-inhibitory domain, but cooperative binding with factors such as PU.1 or SPIB in B cells increases binding affinity, allowing IRF4 to regulate genes containing ETS–IRF composite elements (EICEs; 5'-GGAAnnGAAA-3'). Here we show that in mouse CD4+ T cells, where PU.1/SPIB expression is low, and in B cells, where PU.1 is well expressed, IRF4 unexpectedly can cooperate with activator protein-1 (AP1) complexes to bind to AP1–IRF4 composite (5'-TGAnTCA/GAAA-3') motifs that we denote as AP1–IRF composite elements (AICEs). Moreover, BATF–JUN family protein complexes cooperate with IRF4 in binding to AICEs in pre-activated CD4+ T cells stimulated with IL-21 and in TH17 differentiated cells. Importantly, BATF binding was diminished in Irf4-/- T cells and IRF4 binding was diminished in Batf-/- T cells, consistent with functional cooperation between these factors. Moreover, we show that AP1 and IRF complexes cooperatively promote transcription of the Il10 gene, which is expressed in TH17 cells and potently regulated by IL-21. These findings reveal that IRF4 can signal via complexes containing ETS or AP1 motifs depending on the cellular context, thus indicating new approaches for modulating IRF4-dependent transcription. Genome-wide transcription factors mapping and binding of IRF4, BATF, IRF8, STAT3, JUN etc in WT, Irf4-/- and Batf-/- mice in different cell types (B cells, CD4+ T cells and TH17 cells) cultured with or without IL-21 was conducted. RNA-Seq is conducted in mouse B cells, CD4+ T cells, TH1/TH2/TH9/TH17/Treg.
2012-09-18 | E-GEOD-39756 | biostudies-arrayexpress
Project description:The transcription factors Batf3 and IRF8 are required for development of CD8α+ conventional dendritic cells (cDCs), but the basis for their actions was unclear. Here, we identify two novel Zbtb46+ progenitors that separately generate CD8α+ and CD4+ cDCs and arise directly from the common DC progenitor (CDP). Irf8 expression in the CDP depends on prior PU.1-dependent autoactivation, and specification of pre-CD8 DC progenitors requires IRF8 but not Batf3. However, upon pre-CD8 DC specification, Irf8 autoactivation becomes Batf3-dependent at a CD8α+ cDC-specific enhancer containing multiple AP1-IRF composite elements (AICEs) within the Irf8 superenhancer. CDPs from Batf3-/- mice that specify toward pre-CD8 DCs fail to complete CD8α+ cDC development due to decay of Irf8 autoactivation, and divert to the CD4+ cDC lineage. Examination of histone modifications (H3K27ac and H3K4me1) and 2 transcription factors (Batf3 and Irf8) and the p300 co-factor binding in 3 different dendritic cell subsets
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Project description:Anti-viral CD8 T cell responses are characterized by an initial activation/priming of T lymphocytes followed by a massive proliferation, subset differentiation, population contraction and the development of a stable memory pool. The transcription factor BATF3 has been shown to play a central role in the development of conventional dendritic cells (cDC1), which in turn are critical for the optimal priming of CD8 T cells. Here we show that BATF3 is expressed within the first days after priming but has long-lasting T cell intrinsic effects. We found that T cells that lack Batf3 show a normal expansion and differentiation, yet succumbed to an aggravated contraction and had a diminished memory response. Vice versa BATF3-overexpression in CD8 T cells promoted their survival and transition to memory. Mechanistically, BATF3 regulates T cell apoptosis and longevity via the proapoptotic factor BIM. By programing CD8 T cell survival and memory, BATF3 is a promising molecule to optimize adoptive T cell therapy in patients.
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Project description:Although Bach2 plays an important role in regulating the Th2-type immune response, the underlying molecular mechanisms remain unclear. We herein demonstrate that Bach2 associates with Batf and binds to the regulatory regions of the Th2 cytokine gene loci. The Bach2-Batf complex antagonizes the recruitment of the Batf-Irf4 complex to AP-1 motifs and suppresses Th2 cytokine production. Furthermore, we found that Bach2 regulates the Batf and Batf3 expressions via two distinct pathways. First, Bach2 suppresses the maintenance of the Batf and Batf3 expression through the inhibition of IL-4 production. Second, the Bach2-Batf complex directly binds to the Batf and Batf3 gene loci and reduces transcription by interfering with the Batf-Irf4 complex. These findings suggest that IL-4 and Batf form a positive feedback amplification loop to induce Th2 cell differentiation and the subsequent Th2-type immune response, and Bach2-Batf interactions are required to prevent an excessive Th2 response.
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Project description:Interferon regulatory factor 4 (IRF4) is an IRF family transcription factor with critical roles in lymphoid development and in regulating the immune response. IRF4 binds DNA weakly owing to a carboxy-terminal auto-inhibitory domain, but cooperative binding with factors such as PU.1 or SPIB in B cells increases binding affinity, allowing IRF4 to regulate genes containing ETS–IRF composite elements (EICEs; 5'-GGAAnnGAAA-3'). Here we show that in mouse CD4+ T cells, where PU.1/SPIB expression is low, and in B cells, where PU.1 is well expressed, IRF4 unexpectedly can cooperate with activator protein-1 (AP1) complexes to bind to AP1–IRF4 composite (5'-TGAnTCA/GAAA-3') motifs that we denote as AP1–IRF composite elements (AICEs). Moreover, BATF–JUN family protein complexes cooperate with IRF4 in binding to AICEs in pre-activated CD4+ T cells stimulated with IL-21 and in TH17 differentiated cells. Importantly, BATF binding was diminished in Irf4-/- T cells and IRF4 binding was diminished in Batf-/- T cells, consistent with functional cooperation between these factors. Moreover, we show that AP1 and IRF complexes cooperatively promote transcription of the Il10 gene, which is expressed in TH17 cells and potently regulated by IL-21. These findings reveal that IRF4 can signal via complexes containing ETS or AP1 motifs depending on the cellular context, thus indicating new approaches for modulating IRF4-dependent transcription.
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Project description:Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Phenotypic effects are preceded by the direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4 and the subsequent down-regulation of the IRF4 transcriptional program. Ectopic expression of IRF4 antagonizes the phenotypic effects of CBP/EP300 bromodomain inhibition and prevents the suppression of the IRF4 target c-MYC. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network. Through the use of CBP/EP300 bromodomain inhibitors (CBP/EP300i), we demonstrate that MYC expression in BETi-resistant cells is dependent on CBP/EP300 bromodomains and that treatment with CBP/EP300i restores phenotypic sensitivity.
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Project description:Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Phenotypic effects are preceded by the direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4 and the subsequent down-regulation of the IRF4 transcriptional program. Ectopic expression of IRF4 antagonizes the phenotypic effects of CBP/EP300 bromodomain inhibition and prevents the suppression of the IRF4 target c-MYC. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network. A total of 13 ChIP-seq samples were sequenced. Samples were treated with control (DMSO) or test compound (2.5 uM SGC-CBP30 or 0.25uM CPI267203) for 6 hours. Signal from input samples was included to subtract background signal from each ChIP-seq sample. Antibodies used were against p300, H3K18ac, H3K27ac, or BRD4.
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