BATF-JUN is critical for IRF4-mediated transcription in T cells.
BATF-JUN is critical for IRF4-mediated transcription in T cells.
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干扰素调节因子4 （IRF4）是一种IRF家族转录因子，在淋巴细胞发育和调节免疫应答中起关键作用。由于c端自身抑制结构域，IRF4与DNA的结合较弱，但与B细胞中的PU.1或SPIB等因子的协同结合增加了结合亲和力，使IRF4能够调节含有ETS/IRF复合元件（EICEs; 5 ' -GGAAnnGAAA-3 '）的基因。在这里，我们发现在PU.1/SPIB表达较低的CD4+ T细胞和PU.1表达良好的B细胞中，IRF4意外地可以与激活蛋白-1 （AP-1）复合物结合AP-1/IRF4复合物（TGAnTCA/GAAA）基元，我们将其称为AP-1/IRF复合物元件（AICEs）。此外，在IL-21刺激的预激活CD4+ T细胞和Th17分化细胞中，BATF/Jun家族蛋白复合物与IRF4协同结合AICEs。重要的是，在Irf4−/−T细胞中，BATF结合减少，而在BATF−/−T细胞中，Irf4结合减少，这与这些因子之间的功能合作一致。此外，我们发现AP-1和IRF复合物共同促进Il10基因的转录，Il10基因在Th17细胞中表达，并受到IL-21的有效调控。这些发现表明，IRF4可以根据细胞环境通过包含ETS或AP-1基序的复合物发出信号，从而为调节IRF4依赖性转录提供了新的途径。
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 due to a C-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 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 (AP-1) complexes to bind to AP-1/IRF4 composite (TGAnTCA/GAAA) motifs that we denote as AP-1/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 AP-1 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 AP-1 motifs depending on the cellular context, thus indicating new approaches for modulating IRF4-dependent transcription.
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