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The IRF4 Gene Regulatory Module Functions as a Read-Write Integrator to Dynamically Coordinate T Helper Cell Fate.
Immunity ( IF 25.5 ) Pub Date : 2017-09-19 , DOI: 10.1016/j.immuni.2017.09.001 Veena Krishnamoorthy 1 , Sunil Kannanganat 2 , Mark Maienschein-Cline 3 , Sarah L Cook 1 , Jianjun Chen 4 , Neil Bahroos 3 , Evelyn Sievert 5 , Emily Corse 6 , Anita Chong 4 , Roger Sciammas 1
Immunity ( IF 25.5 ) Pub Date : 2017-09-19 , DOI: 10.1016/j.immuni.2017.09.001 Veena Krishnamoorthy 1 , Sunil Kannanganat 2 , Mark Maienschein-Cline 3 , Sarah L Cook 1 , Jianjun Chen 4 , Neil Bahroos 3 , Evelyn Sievert 5 , Emily Corse 6 , Anita Chong 4 , Roger Sciammas 1
Affiliation
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Transcriptional regulation during CD4+ T cell fate decisions enables their differentiation into distinct states, guiding immune responses toward antibody production via Tfh cells or inflammation by Teff cells. Tfh-Teff cell fate commitment is regulated by mutual antagonism between the transcription factors Bcl6 and Blimp-1. Here we examined how T cell receptor (TCR) signals establish and arbitrate Bcl6-Blimp-1 counter-antagonism. We found that the TCR-signal-induced transcription factor Irf4 is essential for the differentiation of Bcl6-expressing Tfh and Blimp-1-expressing Teff cells. Increased TCR signaling raised Irf4 amounts and promoted Teff cell fates at the expense of Tfh ones. Importantly, orthogonal induction of Irf4 expression redirected Tfh cell fate trajectories toward those of Teff. Mechanistically, we linked greater Irf4 abundance with its recruitment toward low-affinity binding sites within Teff cell cis-regulatory elements, including those of Prdm1. We propose that the Irf4 locus functions as the "reader" of TCR signal strength, and in turn, concentration-dependent activity of Irf4 "writes" T helper fate choice.
中文翻译：
IRF4基因调控模块充当读写整合器，可动态协调T辅助细胞的命运。
CD4 + T细胞命运决定过程中的转录调控使其能够分化为不同的状态，从而引导免疫反应通过Tfh细胞产生抗体或通过Teff细胞产生炎症。Tfh-Teff细胞命运的承诺是由转录因子Bcl6和Blimp-1之间的相互拮抗来调节的。在这里，我们检查了T细胞受体（TCR）信号如何建立和仲裁Bcl6-Blimp-1反拮抗作用。我们发现，TCR信号诱导的转录因子Irf4对于表达Bcl6的Tfh和表达Blimp-1的Teff细胞的分化至关重要。TCR信号的增加增加了Irf4的数量，并促进了Teff细胞的命运，但以Tfh的代价为代价。重要的是，Irf4表达的正交诱导将Tfh细胞的命运轨迹重定向到Teff。机械上，我们将更大的Irf4丰度与其募集到Teff细胞顺式调控元件（包括Prdm1在内）中的低亲和力结合位点联系起来。我们建议Irf4基因座充当TCR信号强度的“读取器”，并且反过来，Irf4的浓度依赖性活动“写入” T辅助细胞的命运选择。
更新日期：2017-09-19
中文翻译：
IRF4基因调控模块充当读写整合器，可动态协调T辅助细胞的命运。
CD4 + T细胞命运决定过程中的转录调控使其能够分化为不同的状态，从而引导免疫反应通过Tfh细胞产生抗体或通过Teff细胞产生炎症。Tfh-Teff细胞命运的承诺是由转录因子Bcl6和Blimp-1之间的相互拮抗来调节的。在这里，我们检查了T细胞受体（TCR）信号如何建立和仲裁Bcl6-Blimp-1反拮抗作用。我们发现，TCR信号诱导的转录因子Irf4对于表达Bcl6的Tfh和表达Blimp-1的Teff细胞的分化至关重要。TCR信号的增加增加了Irf4的数量，并促进了Teff细胞的命运，但以Tfh的代价为代价。重要的是，Irf4表达的正交诱导将Tfh细胞的命运轨迹重定向到Teff。机械上，我们将更大的Irf4丰度与其募集到Teff细胞顺式调控元件（包括Prdm1在内）中的低亲和力结合位点联系起来。我们建议Irf4基因座充当TCR信号强度的“读取器”，并且反过来，Irf4的浓度依赖性活动“写入” T辅助细胞的命运选择。
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