Quality of TCR signaling determined by differential affinities of enhancers for the composite BATF-IRF4 transcription factor complex.
Quality of TCR signaling determined by differential affinities of enhancers for the composite BATF-IRF4 transcription factor complex.
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DOI：
10.1038/ni.3714
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发表时间：
2017-05
影响因子：
30.5
通讯作者：
Murphy KM
中科院分区：
文献类型：
--
作者：
Iwata A;Durai V;Tussiwand R;Briseño CG;Wu X;Grajales-Reyes GE;Egawa T;Murphy TL;Murphy KM
T 细胞受体 (TCR) 信号传导的不同强度会产生不同的结果，但其机制仍不清楚。转录因子 IRF4 的丰度随着 TCR 信号强度的增加而增加，但这如何诱导不同类型的反应尚不清楚。我们将不同 TCR 刺激强度下的 TH2 基因表达与 BATF/IRF4 增强子占据率进行比较。 BATF/IRF4 依赖性基因聚集成不同的 TCR 敏感性。增强子表现出 BATF/IRF4 三元复合物的占据谱，与基因表达的 TCR 敏感性相关。紧邻先前定义的 AICE 基序两侧的 DNA 序列控制 BATF/IRF4 的亲和力，以直接与 DNA 结合。 ChIP-exo 分析允许在与自身免疫抵抗相关的人类 CTLA4 SNP 上鉴定出新的高亲和力 AICE2 基序。因此，不同增强子对 BATF-IRF4 复合物的亲和力可能是响应不同 TCR 信号强度而产生不同信号结果的基础。
Variable strengths of T cell receptor (TCR) signaling can produce divergent outcomes, but the mechanism remains obscure. The abundance of the transcription factor IRF4 increases with TCR signal strength, but how this would induce distinct types of responses is unclear. We compared TH2 gene expression with BATF/IRF4 enhancer occupancy at varying strengths of TCR stimulation. BATF/IRF4-dependent genes clustered into distinct TCR-sensitivities. Enhancers exhibited a spectrum of occupancy by BATF/IRF4 ternary complex that correlated with TCR-sensitivity of gene expression. DNA sequences immediately flanking the previously defined AICE motif controlled the affinity for BATF/IRF4 for direct binding to DNA. ChIP-exo analysis allowed identification of a novel high-affinity AICE2 motif at a human SNP of CTLA4 associated with resistance to autoimmunity. Thus, the affinity of different enhancers for the BATF-IRF4 complex may underlie divergent signaling outcomes in response to various strengths of TCR signaling.