A Genomic Regulatory Element That Directs Assembly and Function of Immune-Specific AP-1–IRF Complexes

Glasmacher, Elke; Agrawal, Sachin; Chang, Amy; Murphy, Theresa L.; Zeng, Wenwen; Lugt, Bryan Vander; Khan, Aly A.; Ciofani, Maria; Spooner, Chauncey J.; Rutz, Sascha; Hackney, Jason A.; Nurieva, Roza; Escalante, Carlos; Ouyang, Wenjun; Littman, Dan R.; Singh, Harinder

doi:10.1126/science.1228309

Cited by 309 publications

(388 citation statements)

References 45 publications

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“…EICE is known to be dually occupied by one of the two Ets factors, PU.1/SPI1 or SPIB, in combination with one of the two IRF factors, IRF4 or IRF8 (51,52). Other Ets/IRF factors do not interact in this fashion (53).…”

Section: Discussionmentioning

confidence: 99%

Dendritic cell fate is determined by BCL11A

Ippolito

Dekker

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

110

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The plasmacytoid dendritic cell (pDC) is vital to the coordinated action of innate and adaptive immunity. pDC development has not been unequivocally traced, nor has its transcriptional regulatory network been fully clarified. Here we confirm an essential requirement for the BCL11A transcription factor in fetal pDC development, and demonstrate this lineage-specific requirement in the adult organism. Furthermore, we identify BCL11A gene targets and provide a molecular mechanism for its action in pDC commitment. Embryonic germ-line deletion of Bcl11a revealed an absolute cellular, molecular, and functional absence of pDCs in fetal mice. In adults, deletion of Bcl11a in hematopoietic stem cells resulted in perturbed yet continued generation of progenitors, loss of downstream pDC and B-cell lineages, and persisting myeloid, conventional dendritic, and T-cell lineages. Challenge with virus resulted in a marked reduction of antiviral response in conditionally deleted adults. Genome-wide analyses of BCL11A DNA binding and expression revealed that BCL11A regulates transcription of E2-2 and other pDC differentiation modulators, including ID2 and MTG16. Our results identify BCL11A as an essential, lineage-specific factor that regulates pDC development, supporting a model wherein differentiation into pDCs represents a primed "default" pathway for common dendritic cell progenitors.

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Section: Discussionmentioning

confidence: 99%

Dendritic cell fate is determined by BCL11A

Ippolito

Dekker

Wang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

110

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“…These results reveal broad cooperative gene regulation by STAT3 and IRF4. In T cells, numerous target genes of IL-21 are regulated through basic leucine zipper transcription factor, ATF-like, JUN, IRF4 and STAT3 (37,38). Notably, these transcription factors are also potential targets through which IL-21 signaling may be regulated.…”

Section: Signaling By Il-21mentioning

confidence: 99%

Advances of the interleukin-21 signaling pathway in immunity and angiogenesis

Yuan

Wang

2016

Biomedical Reports

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Abstract. and its receptor (IL-21R) are broadly expressed on human B cells, activated T cells and other myeloid cells. IL-21 cooperates with IL-6 and transforming growth factor-β to regulate T-cell differentiation. IL-21-mediated human B cell and dendritic cells differentiation requires signal transducer and activator of transcription 3 (STAT3), and also induces B-cell apoptosis dependents on the Toll-like receptor signal. Recently, in vitro and in vivo experiments showed that IL-21/IL-21R regulate angiogenesis through STAT3. IL-21 signaling pathways are complex due to its cooperation with other transcriptional factors, such as interferon regulatory factor 4 and granulocyte-macrophage colony-stimulating factor. The Janus kinase-STAT pathway has been the most extensively studied. With the increase in the understanding of IL-21 biology in the context of each specific disease or pathological condition, IL-21 could be a new therapeutic target for immune-related disease.

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“…In CD4 + T cells, IRF4 is crucial for the differentiation into T helper (Th) subsets such as Th2, Th9, Th17, and Tfh cells (13)(14)(15)(16)(17)(18). Mechanistically, IRF4 controls B-cell and dendritic cell differentiation by cooperative DNA binding with TFs of the Ets family on Ets-IRF composite elements (EICE) as well as by cooperation with basic leucine zipper transcription factor ATF-like (BATF)-JUN heterodimers in binding to AP-1-IRF4 composite elements (AICE) (19)(20)(21)(22)(23). In contrast, differentiation of CD4 + T cells relies mainly on IRF4 binding to AICE elements (19,21,22).…”

mentioning

confidence: 99%

“…Mechanistically, IRF4 controls B-cell and dendritic cell differentiation by cooperative DNA binding with TFs of the Ets family on Ets-IRF composite elements (EICE) as well as by cooperation with basic leucine zipper transcription factor ATF-like (BATF)-JUN heterodimers in binding to AP-1-IRF4 composite elements (AICE) (19)(20)(21)(22)(23). In contrast, differentiation of CD4 + T cells relies mainly on IRF4 binding to AICE elements (19,21,22). Moreover, there is evidence for cooperation of IRF4 with other TFs, including members of the NFAT, STAT, or homeobox protein families (12).…”

mentioning

confidence: 99%

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

Raczkowski

Ritter

Heesch

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Robust cytotoxic CD8 + T-cell response is important for immunity to intracellular pathogens. Here, we show that the transcription factor IFN Regulatory Factor 4 (IRF4) is crucial for the protective CD8 + T-cell response to the intracellular bacterium Listeria monocytogenes. IRF4-deficient (Irf4 −/− ) mice could not clear L. monocytogenes infection and generated decreased numbers of L. monocytogenesspecific CD8 + T cells with impaired effector phenotype and function. Transfer of wild-type CD8 + T cells into Irf4 −/− mice improved bacterial clearance, suggesting an intrinsic defect of CD8 + T cells in Irf4 −/− mice. Following transfer into wild-type recipients, Irf4 −/− CD8 + T cells became activated and showed initial proliferation upon L. monocytogenes infection. However, these cells could not sustain proliferation, produced reduced amounts of IFN-γ and TNF-α, and failed to acquire cytotoxic function. Forced IRF4 expression in Irf4 −/− CD8 + T cells rescued the defect. During acute infection, Irf4 −/− CD8 + T cells demonstrated diminished expression of B lymphocyte-induced maturation protein-1 (Blimp-1), inhibitor of DNA binding (Id)2, and T-box expressed in T cells (T-bet), transcription factors programming effector-cell generation. IRF4 was essential for expression of Blimp-1, suggesting that altered regulation of Blimp-1 contributes to the defects of Irf4 −/− CD8 + T cells. Despite increased levels of B-cell lymphoma 6 (BCL-6), Eomesodermin, and Id3, Irf4 −/− CD8 + T cells showed impaired memory-cell formation, indicating additional functions for IRF4 in this process. As IRF4 governs B-cell and CD4 + T-cell differentiation, the identification of its decisive role in peripheral CD8 + T-cell differentiation, suggests a common regulatory function for IRF4 in adaptive lymphocytes fate decision.

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A Genomic Regulatory Element That Directs Assembly and Function of Immune-Specific AP-1–IRF Complexes

Cited by 309 publications

References 45 publications

Dendritic cell fate is determined by BCL11A

Dendritic cell fate is determined by BCL11A

Advances of the interleukin-21 signaling pathway in immunity and angiogenesis

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

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A Genomic Regulatory Element That Directs Assembly and Function of Immune-Specific AP-1–IRF Complexes

Cited by 309 publications

References 45 publications

Dendritic cell fate is determined by BCL11A

Dendritic cell fate is determined by BCL11A

Advances of the interleukin-21 signaling pathway in immunity and angiogenesis

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

Contact Info

Product

Resources

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